Small molecule potentiators of metabotropic glutamate receptors I

ABSTRACT

The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The present invention thus provides compounds of formula I 
                         
and variables defined herein.

CROSS-REFERENCE TO RELATED APPLICATION

This is the non-provisional of U.S. Provisional Patent Application No. 61/318,868, filed on Mar. 30, 2010, the contents of which are hereby incorporated by reference.

The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved.

BACKGROUND OF THE INVENTION

Glutamate, the major excitatory neurotransmitter in the brain, elicits its effects by activating ligand-gated cation channels, termed ionotropic glutamate receptors (iGluRs), as well as metabotropic glutamate receptors (mGlu receptors). The latter belong to the G-Protein coupled receptor (GPCR) family 3 (Conn and Pin, Annu. Rev. Pharmacol. Toxicol. 37, 205-37, 1997) and are coupled through heterotrimeric G-proteins to intracellular effector systems. These receptor types exert multiple modulatory effects within the central nervous system (CNS). Eight mGlu receptor subtypes have been cloned from mammalian brain to date. Depending on their G-protein coupling profile, pharmacology and sequence identity, these receptors are classified into three groups (Conn and Pin, Annu. Rev. Pharmacol. Toxicol. 37, 205-37, 1997). Group I mGlu receptors primarily couple through Gq to increases in phosphoinositide hydrolysis and the cellular Ca²⁺-system via phospholipase C (PLC), and include the mGlu1 receptor and mGlu5 receptor. Group II mGlu receptors, which include mGlu2 and mGlu3, inhibit adenylylcyclase (AC), just as group III mGlu receptors, which comprise mGlu4, mGlu6, mGlu7 and mGlu8. Thereby, in groups II and III, the pertussis-toxin sensitive G-protein Gi is involved in signal transduction. However, group II and group III mGlu receptors differ in their sequence identity and pharmacological profile.

Of the 8 mGlu receptor subtypes various splice variants exist. Within group I mGlu receptors the splicing variability is most pronounced. MGlu1 exists in 6 different splicing forms. The receptors mGlu1a/a, 1b/b, 1c, 1d and 1f all differ in their C-terminal, intracellular domain (Prezeau et al., Mol. Pharmacol. 49, 422-429, 1996; Soloviev et al., Biochimica et Biophysica Acta 1446, 161-166, 1999), and mGlu1e is truncated N-terminally, lacking most of the protein coding region (Pin and Duvoisin, Neuropharmacol. 34, 1-26, 1995). So far of mGlu5 (group I), and the group III receptors mGlu4, mGlu7 and mGlu8 two splicing variants have been demonstrated. mGlu6 which is located solely in ON-bipolar cells of the retina (Nakanishi et al., Brain Res. Rev. 26, 230-235, 1998), only has one isoform. The same holds for mGlu2 and mGlu3 receptors (Fagni et al., TINS 23 (2), 80-88, 2000).

The synaptic localization of group I mGlu receptors and group II/III mGlu receptors differs. While group I receptors are located predominantly postsynaptically, group III mGlu receptors rather show a presynaptic localization (Shigemoto et al., J. Neurosci. 17, 7503-7522, 1997; Cartmell & Schoepp, J. Neurochem. 75(3), 889-907, 2000). Group II receptors seem to be located pre- and postsynaptically, depending on brain region and synapse-type. A perisynaptic localization of mGlu2 has also been demonstrated. In this case, the receptor might only be activated under high frequency stimulation, then preventing further transmitter release and thus reducing pathologically high levels of glutamate within the synaptic cleft. Autoreceptor function (medial perforant path, mossy fiber-CA3, spinal cord synapse, corticostriatal synapse) and heteroreceptor functions have been demonstrated for group II mGlu receptors at synapses in diverse brain regions. The pre- and perisynaptic localization of group II mGlu receptors, combined with their auto- and heteroreceptor function and their coupling to inhibitory intracellular signalling cascades implies an important role of this receptor type for the regulation of excitatory neurotransmission.

The first compounds which discriminated between the 3 different groups of mGlu receptors were low affinity agonists: 3,5-dihydroxyphenylglycine (3,4-DHPG), which selectively stimulates the group 1 mGlu receptors; (2R,4R)-4-aminopyrrolidine-carboxylic acid (2R,4R-APDC) activating group II mGlu receptors (Monn et al., J. Med. Chem. 39(15), 2990-3000, 1996) and L-Amino-4-phosphonobutyrate (L-AP4, Trombley and Westbrook, J. Neurosci. 12(6), 2043-50, 1992) for the activation of group III mGlu receptors. All these compounds have been valuable tools for the investigation of the various functions of mGlu receptors by in vitro studies, but none of these compounds has been shown to exert potent central effects after systemic administration. Other early compounds, which have mainly been used for in vitro studies, turned out to activate ionotropic glutamate receptors as well. For the widely used group II mGlu receptor agonist (2S, 1′R, 2′R, 3′R)-2-(2′,3′-dicarboxypropyl)glycine also activates NMDA receptors.

For studying the in vivo effects and therapeutic applications of group II agonists, the breakthrough came from the discovery of LY354740 and LY379268 (Formulae given e.g. in D. A. Barda et al., Bioorganic and Medicinal Chemistry Letters, 14, 3099-3102, 2004). These two compounds are highly specific group II receptor agonists with only very low affinity to other mGlu receptors or ionotropic glutamate receptors. They have EC₅₀ values of 10 and 20 nM (LY354740) and 3 and 5 nM (LY379268), for mGlu2 and 3 respectively. While a differentiation between the two group II receptors is not possible, a specificity of >1:30.000 towards group I receptors and between 1:100 (mGlu6) to >1:30.000 (mGlu7) to group III receptors offers a high discrimination potential to these receptor types (Cartmell and Schoepp, J. Neurochem. 75(3), 889-907, 2000; Bräuner-Osborne et al., J. Med. Chem. 43 (14), 2609-2645, 2000). Both compounds were designed as conformationally constrained analogues of glutamate (Monn et al., J. Med. Chem. 40(4), 528-37, 1997; J. Med. Chem. 42(6), 1027-40, 1999), and represent competitive agonists at the glutamate binding site. Furthermore these two compounds are systemically active.

Derivatives of these compounds, MGS 0008 and MGS 0028 (Nakazato et al., J. Med. Chem. 43(25), 4893-909, 2000) and have a higher oral availability. They also show increased antagonistic effects on PCP-induced head-weaving and hyperactivity in rats. Recently also a highly selective antagonist for group II mGlu receptors has been identified (Kingston et al., Neuropharmacology 37(1), 1-12, 1998; Johnson et al., Neuropharmacology 38(10), 1519-29, 1999). No appreciable specific binding of the radio-ligand [3H]-LY341495 (formula given in D. A. Barda et al. 2004) was found in membranes of cells expressing human mGlu1a, mGlu5a, mGlu4a, mGlu6, or mGlu7a receptors. Many effects induced by group II receptor agonists could be reversed by this compound. Thus LY341495 also represents a highly selective tool compound.

Positive modulators activate the mGlu2 receptor dependent on the presence of glutamate (potentiators). Thus, the compound “sensitizes” the receptor to react already at lower concentrations of the ligand. Positive modulators can also activate the mGlu2 receptor directly. The mGlu receptors consist of a large extracellular N-terminal domain, which binds the natural ligand, glutamate, which is homologous to the periplasmatic amino acid binding proteins from bacteria. This domain is linked to a 7-transmembrane domain. This canonical domain, common to all G-protein coupled receptors, contains the canonical ligand binding site for GPCRs (compare rhodopsin in retinal). In the mGluRs this site is free and may play a role as modulatory site for positive and negative allosteric compounds.

A hint for the exact amino acid sites responsible for ligand binding of a model potentiator (LY487379, see Johnson et al., J. Med. Chem. 46(15), 3189-92, 2003) come from the amino acid comparison between mGlu2 receptor and mGluR3 in this region. As the potentiator is specific for mGlu2 receptor, the binding should not take place at mGluR3 and the responsible amino acids should be exactly the ones which differ between the two receptors. Recently the binding site of a model potentiator (LY487379) has been mapped by site directed mutagenesis. The binding site seems to be within the transmembrane domain of mGlu2 receptor (Schaffhauser et al., Mol. Pharmacol. 64(4), 798-810, 2003). In particular the amino acids 688, 689 and 735 are indicated for binding.

MGlu2 receptor is expressed in both separate and overlapping circuits of relevance for neuropsychiatric and neurological disorders. This includes expression in neocortex, thalamus, striatum, amygdala and hippocampus. Within these circuits mGlu2 receptor is mainly expressed presynaptically. As a consequence of this expression pattern it has been shown that excitatory transmitter release is regulated by group II agonists in diverse brain regions. For, it has been demonstrated that group II agonists normalize PCP-induced increase of glutamate in the prefrontal cortex (PFC) and that dopamine is regulated by group II agonists in a region-specific manner. As one function group II agonists increase dopamine and metabolites in the PFC. Also serotonin and metabolites are regulated in the PFC. This has further been demonstrated by a functional antagonism of 5-HT2A receptors in this brain region.

These data indicate that the mGlu2 receptor approach may normalize a number of de-regulated transmitters in schizophrenia. The mGlu2 receptor agonist/potentiator concept will likely give rise to the opportunity to normalize

-   -   positive symptoms, due to regulation of glutamate,     -   negative symptoms, due to regulation of dopamine and serotonin,         and     -   cognitive symptoms, due to regulation of acetylcholine in the         PFC.         Besides schizophrenia, drug abuse may be an interesting disease         indication, as group II agonists block of expression of         locomotor sensitization by amphetamine, among a multitude of         other described effects. The usefulness of such compounds is not         limited to the disease states described above.

The potentiator concept for mGlu2 receptor is relatively new (Barda et al., 2004), but necessary to evaluate the relevance of mGlu2 receptor versus mGluR3. This is of note, as the group II agonists described above do cross react with both receptor types. Within the recent years, reports directly demonstrate the relevance of mGlu2 receptor in psychosis models in rodents by describing function of mGlu2 receptor potentiators in models of PCP-induced hyperlocomotion, amphetamine-induced hyperlocomotion, and reversal of amphetamine-induced disruption of PPI in mice (Galici et al., JPET 315(3), 1181-1187, 2005).

Beyond these data, indicating a relevance of mGlu2 receptor potentiators in schizophrenia, new reports furthermore demonstrate efficacy of mGlu2 receptor potentiators in anxiety, as potentiators have been shown to be efficacious in rat fear-potentiated startle and stress-induced hyperthermia in mice (Johnson et al. Psychopharmacol, 179(1), 271-83, 2005).

A pure NMDA activation approach (the “glutamatergic hypothesis of schizophrenia”) may result in side effect liabilities. In particular excitotoxicity is a relevant side effect which needs to be considered early within a potential screening cascade of such projects. This side effect liability may limit the usefulness of such approaches.

As described above, the mGlu2 receptor positive modulator approach does not purely rely on the glutamatergic hypothesis, but likely is involved in the normalization of release of a number of excitatory neurotransmitters. Consequently, to date there is no evidence for excitotoxic liability of group II agonists or mGlu2 receptor positive modulators. Group II agonists even show the opposite effects. They are neuroprotective in the MPTP model of Parkinson's disease, they reduce low Mg²⁺-induced epileptiform discharges in slice preparations and they have anticonvulsant action in acute seizure models.

As a relevant side effect, a negative influence on cognition was described for group II agonists (Higgins et al., Neuropharmacol 46, 907-917, 2004). However, to date this finding is controversial in the literature. While one group finds a reversal of cognitive deficits induced by PCP (Moghaddam and Adams, Science 281(5381), 1349-52, 1998), a second group finds a reduction of DNMTP performance with the mGlu2 receptor agonist LY354740, which is not present in mGlu2 receptor knockout mice (Higgins et al., Neuropharmacol. 46, 907-917, 2004). This finding contrasts to the data from Moghaddam and Adams and would also contradict the normalization of ACh release in the PFC by this compound (see above).

WO 2006/015158 and WO 2006/047237 describe heterocyclic compounds carrying an indanone moiety, the compounds being potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/030032 describes pyridinone compounds which are potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/049969 describes N-(phenyl)aminoalkyl substituted pyrimidine compounds, which are potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/057860, WO 2006/057869 and WO 2006/057870 describe compounds carrying a 4-acyl-3-hydroxy-phenyl moiety. The compounds are suggested to be potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/091496 describes compounds carrying a benzazole moiety, the compounds being suggested as potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/020879, WO2007/021308 and WO 2007/021309 disclose isoindolone compounds, which are suggested as potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.

WO 2008/145616 discloses heterocyclic compounds which are positive modulators of metabotropic receptors, including the mGlu2 receptor.

WO 2008/130853 discloses heterocyclic hydrazides and their use as metabotropic glutamate receptor potentiators.

Although the compounds of prior art have a high affinity with regard to the mGlu2 receptor, their receptor binding profile and/or their pharmacological profile is not always satisfactory. In particular, the compounds often have poor selectivity with regard to mGlu2 receptor in comparison with mGlu3 or group III mGlu receptors or are glutamate agonists. Moreover, the potentiators are in terms of (i) binding affinity, (ii) receptor potentiation and/or stimulation profile, (iii) selectivity versus other receptors, (iv) physicochemical properties, (v) in vitro microsomal stability and (vi) pharmacokinetic parameters suboptimal.

It is an object of the present invention to provide further compounds which are potentiators of metabotropic glutamate receptors, in particular of the mGlu2 receptor, and which thus are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. In particular, such diseases are central nervous system disorders selected from the group of schizophrenia, drug abuse, anxiety, migraine, depression and epilepsy and the like.

These and further objects are solved by the compounds of the general formula I, as described herein, as well as by the N-oxides thereof, and by their pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION

The present invention thus provides compounds of formula I

wherein

-   -   X² is N or C—R²     -   X³ is N or C—R³     -   X⁴ is N or C—R⁴     -   provided that none or one of X², X³ or X⁴ is N;     -   Y¹ is N, C or C—R⁵     -   Y² is N, C or C—R⁶     -   Y³ is N, C or C—R⁷     -   Y⁴ is N, C or C—R⁸     -   provided that only the moiety Y¹, Y², Y³ or Y⁴ to which Z is         bound is C and Y², further provided at most one of Y¹, Y², Y³ or         Y⁴ is N;     -   Z is O, S, S(O), S(O)₂ or NR^(Z);         -   R^(Z) is hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,             C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, which is unsubstituted             or carries one radical selected from C₁-C₄-alkoxy and             NR^(Z1)R^(Z2);             -   where R^(Z1) and R^(Z2) are independently of each other                 selected from hydrogen, C₃-C₆-cycloalkyl,                 C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and                 C₁-C₄-alkoxy-C₁-C₄-alkyl, or             -   R^(Z1) and R^(Z2) together with the nitrogen to which                 they are attached form a 5- or 6-membered N-bound                 saturated heterocycle, which, in addition to the                 nitrogen atom may comprise a further heteroatom,                 selected from O, S and N as ring member and which is                 unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl                 radicals;         -   or R^(Z) is a radical SO₂R^(Z3) or a radical             S(O)₂NR^(Z4)R^(Z5);             -   where R^(Z3) is C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,                 C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,                 C₃-C₆-cycloalkylmethyl, phenyl or benzyl, wherein the                 phenyl ring in the last two mentioned radicals itself is                 unsubstituted or carries 1, 2, 3, 4 or 5 identical or                 different radicals selected from halogen, C₁-C₄-alkyl,                 C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,             -   R^(Z4) and R^(Z5) have one of the meanings given for                 R^(Z1) and R^(Z2);     -   Q is CH₂ or CH₂CH₂, where one or two of the hydrogen atoms in         CH₂ or CH₂CH₂ may be replaced by halogen, C₁-C₄-alkyl or         C₁-C₄-haloalkyl;     -   R¹ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,         C₁-C₆-alkoxy, C₁-C₄-haloalkoxy, C₃-C₈-cycloalkyl, a radical         NR^(1a)R^(1b), C-bound 3- to 7-membered, saturated heterocyclyl         having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected         from O and S, as ring members, aryl, aryl-CH₂, aryloxy, hetaryl,         hetaryloxy or hetaryl-CH₂, wherein the heterocyclyl, aryl and         hetaryl rings ring in the last seven radicals themselves are         unsubstituted or carry 1, 2, 3, 4 or 5 identical or different         radicals R^(1c);         -   R^(1a) is hydrogen, C₁-C₈-alkyl, C₁-C₈-haloalkyl,             C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl,             C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, benzyl, phenyl or             5- or 6-membered hetaryl, wherein the phenyl and hetaryl             rings in the last three radicals itself are unsubstituted or             carry 1, 2, 3, 4 or 5 identical or different radicals             R^(1c);         -   R^(1b) is hydrogen or C₁-C₄-alkyl; or         -   NR^(1a)R^(1b) is a 3- to 10-membered, in particular 5- to             10-membered, mono- or bicyclic N-bound saturated             heterocycle, which, in addition to the nitrogen atom may             comprise a further heteroatom, selected from O, S and N as             ring member and which is unsubstituted or carries 1, 2, 3 or             4 radicals R^(1c);         -   R^(1c) is selected from the group consisting of halogen, CN,             OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl,             C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular             C₁-C₄-alkyl;     -   R², R³ and R⁴ are, independently of each other, selected from         hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,         C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,         phenyl, C₁-C₄-haloalkoxy, a radical (CH₂)_(n)NR′R″, where R′ and         R″ have one of the meanings given for R^(Z1) and R^(Z2) and         wherein n is 0, 1, 2, 3 or 4,         -   or C-bound 3- to 10-membered, in particular 3- to 7-membered             saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or             1 heteroatoms, selected from O and S, as ring members, where             the heterocyclyl itself is unsubstituted or carries 1, 2, 3,             4 or 5 identical or different radicals R^(6c), where R^(6c)             has one of the meanings given for R^(1c);     -   R⁵ is hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,         C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkoxy,         (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given         for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, in         particular 1,         -   or C-bound 3- to 10-membered, in particular 3- to 7-membered             saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or             1 heteroatoms, selected from O and S, as ring members, where             the heterocyclyl itself is unsubstituted or carries 1, 2, 3,             4 or 5 identical or different radicals R^(6c), where R^(6c)             has one of the meanings given for R^(1c);     -   R⁶, R⁷, R⁸ are, independently of each other, selected from         hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,         C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,         (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given         for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4,         -   or C-bound 3- to 10-membered, in particular 3- to 7-membered             saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or             1 heteroatoms, selected from O and S, as ring members, where             the heterocyclyl itself is unsubstituted or carries 1, 2, 3,             4 or 5 identical or different radicals R^(6c) where R^(6c)             has one of the meanings given for R^(1c);     -   R^(a) is C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkyl, which         is unsubstituted or carries one radical selected from         C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and a radical NR^(a1)R^(a2),         -   where R^(a1) and R^(a2) are independently of each other             selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,             C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl,         -   a radical NR^(a3)R^(a4) or a radical N═C(R^(a5))R^(a6),             where         -   R^(a3) and R^(a5) are independently of each other selected             from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,             C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and             C₁-C₄-alkoxy-C₁-C₄-alkyl;         -   R^(a4) and R^(a6) are independently of each other selected             from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,             C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl,             C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 10-membered, in             particular 3- to 7-membered saturated heterocyclyl, 3- to             10-membered, in particular 3- to 7-membered saturated             heterocyclylmethyl, where heterocyclyl in the last two             mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1             heteroatoms, selected from O and S, as ring members,             -   aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the                 heterocyclyl, aryl and hetaryl rings ring in the last                 six radicals themselves are unsubstituted or carry 1, 2,                 3, 4 or 5 identical or different radicals R^(ac) where                 R^(ac) has one of the meanings given for R^(1c);     -   R^(b) is hydrogen, halogen or C₁-C₄-alkyl;     -   and the N-oxides and the pharmaceutically acceptable salts         thereof.

The compounds of the present invention are potentiators of metabotropic glutamate (mGlu) receptor function, in particular they are potentiators of mGlu2 receptors. That is, the compounds of the present invention do not appear to bind at the glutamate recognition site on the mGlu receptor, but in the presence of glutamate or a glutamate agonist, the compounds of the present invention increase mGlu receptor response. The present potentiators are expected to have their effect at mGlu receptors by virtue of their ability to increase the response of such receptors to glutamate or glutamate agonists, enhancing the function of the receptors. It is recognized that the compounds of the present invention would be expected to increase the effectiveness of glutamate and glutamate agonists of the mGlu2 receptor. Thus, the compounds of the present invention are expected to be useful in the treatment of various neurological and psychiatric disorders associated with glutamate dysfunction described to be treated herein and others that can be treated by such positive modulators as are appreciated by those skilled in the art.

The present invention also relates to pharmaceutical compositions comprising at least one compound of the formula I, an N-oxide thereof and/or a pharmaceutically acceptable salt thereof, optionally together with at least one physiologically acceptable carrier or auxiliary substance.

The present invention also relates to a method for treating a medical disorder, selected from neurological and psychiatric disorders associated with glutamate dysfunction, said method comprising administering an effective amount of at least one compound of the formula I, an N-oxide thereof and/or a pharmaceutically acceptable salt thereof to a subject in need thereof.

The present invention also relates to a method for potentiation of metabotropic glutamate receptor activity in a mammal which comprises administering an effective amount of at least one compound of the formula I, an N-oxide thereof and/or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of the compounds of formula I, an N-oxide thereof and/or a pharmaceutically acceptable salt thereof, in therapy of a disease mentioned herein.

The compounds of the formula I, their N-oxides and their pharmaceutically acceptable salts are particularly useful for preparing

-   -   a medicament for treating, controlling, ameliorating or reducing         the risk of anxiety in a mammalian;     -   a medicament for preparing a medicament for treating,         controlling, ameliorating or reducing the risk of depression in         a mammalian; a medicament for treating, controlling,         ameliorating or reducing the risk of migraine in a mammalian;     -   a medicament for treating, controlling, ameliorating or reducing         the risk of schizophrenia in a mammalian;     -   a medicament for treating, controlling, ameliorating or reducing         the risk of epilepsy in a mammalian;     -   a medicament for treating or ameliorating the symptoms         associated with substance-related disorders in a mammalian.

The present invention also relates to

-   -   a method for treating, controlling, ameliorating or reducing the         risk of anxiety in a mammalian;     -   a method for treating, controlling, ameliorating or reducing the         risk of depression in a mammalian;     -   a method for treating, controlling, ameliorating or reducing the         risk of schizophrenia in a mammalian;     -   a method for treating, controlling, ameliorating or reducing the         risk of epilepsy in a mammalian;     -   a method for treating, controlling, ameliorating or reducing the         risk of migraine in a mammalian;     -   a method for treating or ameliorating the symptoms associated         with substance-related disorders in a mammalian;

which methods comprising administering an effective amount of at least one compound of the formula I, an N-oxide thereof and/or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated, so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the conversion of the enantiomeric mixture of compounds I into a diastereomeric mixture, e.g. by reaction with a chiral auxiliary, such as a chiral acid or base, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The enantiomeric mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

The term “pharmaceutically acceptable salts” refers to cationic or anionic salts compounds, wherein the counter ion is derived from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.

When the compound of formula I is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts, wherein the counter ion is aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc ion and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium ions. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, trifluoroacetic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of formula I are meant to also include the pharmaceutically acceptable salts.

The present invention moreover relates to compounds of formula I as defined above, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by ¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.

Of course, the compounds according to the invention contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds I.

The compounds of the formula I and their salts in the solid form may exist in more than one crystal structure (polymorphism), and may also be in the form of hydrates or other solvates. The present invention includes any polymorph of the compound I or its salt as well as any hydrate or other solvate.

The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix C_(n)-C_(m) indicates in each case the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties of alkoxyalkyl, alkylamino, dialkylamino and alkylsulfonyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 8 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 2 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylpentyl, n-octyl, 1-methyloctyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl and 2-propylpentyl.

The term “haloalkyl” as used herein and in the haloalkyl moieties of haloalkylsulfonyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 8 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from C₁-C₄-haloalkyl, more preferably from C₁-C₂-haloalkyl, in particular from C₁-C₂-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl or C₁-C₄-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoro-1-trifluormethylethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and the like.

The term “alkoxy” as used herein denotes in each case a straight-chain or branched alkyl group which is bound via an oxygen atom and has usually from 1 to 8 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert-butyloxy, pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 2,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropyloxy, 1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy, 1-ethyl-2-methylpropyloxy n-heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy, 1-ethylpentyloxy, 2-ethylpentyloxy, 3-ethylpentyloxy, 1-propylpentyloxy, n-octyloxy, 1-methyloctyloxy, 2-methylheptyloxy, 1-ethylhexyloxy, 2-ethylhexyloxy, 1,2-dimethylhexyloxy, 1-propylpentoxy and 2-propylpentyloxy.

The term “haloalkoxy” as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 8 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C₁-C₄-haloalkoxy, in particular C₁-C₂-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluorethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and the like.

The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein denotes in each case a straight-chain or branched alkyl group which is bound via an oxygen atom to another alkyl group. Both alkyl groups have usually from 1 to 4 carbon atoms, frequently from 1 to 3 carbon atoms, preferably 1 to 2 carbon atoms. Examples are methoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-n-butyl, ethoxymethyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-n-butyl, n-propoxymethyl, n-propoxyethyl, n-propoxy-n-propyl, n-propoxy-n-butyl, n-butoxymethyl, n-butoxyethyl, n-butoxy-n-propyl, n-butoxy-n-butyl.

The term “cycloalkyl” as used herein denotes in each case a mono- or bicyclic cycloaliphatic radical having usually from 3 to 8 C atoms or 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, and bicycle[2.2.2]octyl.

The term “cycloalkylmethyl” as used herein denotes in each case a methyl radical which is bound to a cycloalkyl group as defined above. Examples are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, especially cyclopropylmethyl.

The term “aryl” as used herein denotes in each case a cyclic radical selected from the group consisting of mono-, bi- or tricyclic aromatic radicals. Examples are phenyl, naphthyl and anthracyl, especially phenyl.

The term “aryl-CH₂” as used herein denotes in each case a methyl radical, which is bound to an aryl group as described above. Examples are benzyl, naphthylmethyl and anthracylmethyl, especially benzyl.

The term “aryloxy” as used herein denotes in each case an aryl group which is bound via an oxygen atom. Examples are phenoxy, naphthoxy and anthracyloxy, especially phenoxy.

The term “hetaryl” as used herein denotes in each case a heterocyclic radical selected from the group consisting of monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S. Examples of 5- or 6-membered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2- or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4-oxadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g. 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl.

The term “hetaryl-CH₂” as used herein denotes in each case a methyl radical, which is bound to a hetaryl group as described above. Examples are methylpyridyl, i.e. 2-, 3-, or 4-methylpyridyl, methylpyrimidinyl, i.e. 2-, 4- or 5-methylpyrimidinyl, methylpyrazinyl, methylpyridazinyl, i.e. 3- or 4-methylpyridazinyl, methylthienyl, i.e. 2- or 3-methylthienyl, methylfuryl, i.e. 2- or 3-methylfuryl, methylpyrrolyl, i.e. 2- or 3-methylpyrrolyl, methyloxazolyl, i.e. 2-, 3- or 5-methyloxazolyl, methylisoxazolyl, i.e. 3-, 4- or 5-methylisoxazolyl, methylthiazolyl, i.e. 2-, 3- or 5-methylthiazolyl, methylisothiazolyl, i.e. 3-, 4- or 5-methylisothiazolyl, methylpyrazolyl, i.e. 1-, 3-, 4- or 5-methylpyrazolyl, i.e. 1-, 2-, 4- or 5-methylimidazolyl, methyloxadiazolyl, methylthiadiazolyl, methyltriazolyl and methyltetrazolyl, i.e. 1H- or 2H-tetrazolyl.

N-bound heterocycles comprise saturated, non-aromatic heterocyclic rings, which are bound via the nitrogen-ring atom. It is 3- to 10-membered and mono- or bicyclic, especially it is a 3- to 7-membered monocyclic ring. Examples therefore include aziridinyl, azetidinyl, azepanyl, azocanyl, azonanyl, azecanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, diazepanyl, diazocanyl, diazonanyl, diazecanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, oxazinanyl, oxazepanyl, oxazocanyl, oxazonanyl, oxazecanyl, thiazolidinyl, isothiazolidinyl, thiazinanyl, thiomorpholinyl, thiazepanyl, thiazocanyl, thiazonanyl, thiazecanyl, oxadiazinanyl, oxadiazepanyl, oxadiazocanyl, oxadiazonanyl, oxadiazecanyl, thiodiazinanyl, thiadiazepanyl, thiadiazocanyl, thiadiazonanyl, thiadiazecanyl, decahydroquinolinyl, decahydroquinazolinyl, deachydronathyridinyl and the like.

The term “C-bound saturated heterocyclyl” as used herein denotes in each case a C-bound heterocyclic radical which is 3- to 10-membered, saturated and having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members. Especially it is 3- to 7-membered, monocyclic radical having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members. The heterocyclyl itself can be unsubstituted or substituted. Examples therefore include aziridinyl, azetidinyl, azepanyl, azocanyl, azonanyl, azecanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, diazepanyl, diazocanyl, diazonanyl, diazecanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, oxazinanyl, oxazepanyl, oxazocanyl, oxazonanyl, oxazecanyl, thiazolidinyl, isothiazolidinyl, thiazinanyl, thiomorpholinyl, thiazepanyl, thiazocanyl, thiazonanyl, thiazecanyl, oxadiazinanyl, oxadiazepanyl, oxadiazocanyl, oxadiazonanyl, oxadiazecanyl, thiodiazinanyl, thiadiazepanyl, thiadiazocanyl, thiadiazonanyl, thiadiazecanyl, decahydroquinolinyl, decahydroquinazolinyl, deachydronathyridinyl and the like.

Preferred compounds of the invention are those, wherein the variables R¹, R^(a), R^(b), Q, Z, X², X³ and X⁴ in formula I independently of each other preferably in any combination have one of the following meanings:

The radical R¹ is selected from the group consisting of hydrogen, halogen, in particular chlorine or bromine, C₁-C₆-alkyl, in particular branched C₃-C₆-alkyl such as isopropyl, isobutyl or tert.-butyl, C₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂, CH₂CF₃ or CF₂CF₃, C₁-C₆-alkoxy, in particular C₁-C₃-alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, C₁-C₄-haloalkoxy, in particular C₁-C₂-fluoroalkoxy, such as OCF₃ or OCHF₂, C₃-C₈-cycloalkyl, in particular C₃-C₆-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a radical NR^(1a)R^(1b), wherein R^(1a) and R^(1b) are as defined above and wherein at least one of R^(1a) and R^(1b), in particular both R^(1a) and R^(1b), are different from hydrogen, aryl, in particular phenyl, aryl-CH₂, in particular benzyl, aryloxy, in particular phenoxy, and hetaryl, in particular pyridinyl, pyrimidinyl, thienyl or furyl, wherein the aryl, in particular phenyl ring, and hetaryl rings in the aforementioned four radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(1c).

In a particular embodiment of the invention, R¹ is selected from the group consisting of phenyl and phenoxy, wherein the phenyl ring in the last two radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(1c).

In another particular embodiment of the invention, R¹ is selected from the group consisting of branched C₃-C₆-alkyl, such as tert.-butyl, C₁-C₆-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl and C₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂, CH₂CF₃ or CF₂CF₃.

In another particular embodiment of the invention, R¹ is linear C₁-C₆-alkyl such as methyl, ethyl, n-propyl or n-butyl.

In another particular embodiment of the invention, R¹ is halogen such as iodine, or chlorine.

In a further particular embodiment of the invention, R¹ is a radical NR^(1a)R^(1b) or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatom, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(1c). In this further particular embodiment, R¹ is especially a radical NR^(1a)R^(1b), where R^(1a) is selected from 2-methoxyethyl, 3-methoxy-n-propyl or 2-ethoxyethyl while R^(1b) is methyl or ethyl or the radical NR^(1a)R^(1b) is morpholinyl, 1,4-oxazepan-4-yl, 4-methylpiperazinyl, 1-pyrrolidinyl or 1-piperidinyl or R¹ is 4-methylpiperidin-1-yl or 3-methylpyrrolidin-1-yl.

Particular examples of R¹ include CF₃, chloro, fluoro, iodo, amino, tert.-butyl, benzylamino, phenylamino, phenoxy, phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholin-4-yl, 1,4-oxazepan-4-yl, 4-methylpiperazin-1-yl, 1-pyrrolidinyl, 1-piperidinyl, 4-methylpiperidin-1-yl, 3-methylpyrrolidin-1-yl, N-(2-methoxyethyl)-N-methylamino, N-(3-methoxy-n-propyl)-N-methylamino, N-(2-ethoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino, N-(3-methoxy-n-propyl)-N-ethylamino or N-(2-ethoxyethyl)-N-ethylamino.

Where present, R^(1a) is particularly selected from the group consisting of hydrogen, C₃-C₈-cycloalkyl, C₁-C₈-alkylcarbonyl, in particular 2,2-dimethylpropionyl, C₁-C₈-alkoxycarbonyl, in particular tert-butoxycarbonyl, benzyl, phenyl or 5- or 6-membered hetaryl, wherein the phenyl and hetaryl rings in the last three radicals itself are unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(1c).

Where present, R^(1b) is preferably hydrogen or C₁-C₄-alkyl.

Where present, NR^(1a)R^(1b) may also preferably be a 5- to 10-membered, in particular 5- or 6-membered, mono- or bicyclic N-bound saturated heterocycle, which, in addition to the nitrogen atom may comprise a further heteroatom selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals, examples including 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidinyl, N-methylpiperazin-1-yl, 1,4-oxazepan-4-yl, 4-methylpiperidin-1-yl or 3-methylpyrrolidin-1-yl.

R^(1a) may also preferably be C₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(1b) is C₁-C₄-alkyl. Examples are N-(2-methoxyethyl)-N-methylamino, N-(3-methoxy-n-propyl)-N-methylamino, N-(2-ethoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino, N-(3-methoxy-n-propyl)-N-ethylamino and N-(2-ethoxyethyl)-N-ethylamino.

Where present, R^(1c) is selected from the group consisting of halogen, CN, OH, C₁-C₄-alkyl, such as methyl, ethyl, n-propyl or isopropyl, C₃-C₆-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C₁-C₄-haloalkyl, in particular CHF₂, CF₃, CH₂CF₃ or CF₂CF₃, C₁-C₄-alkoxy, in particular methoxy or ethoxy, and C₁-C₄-haloalkoxy.

The radical R^(a) is selected from the group consisting of C₃-C₆-cycloalkyl, in particular C₃-C₄-cycloalkyl, such as cyclopropyl, C₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl such as CF₃, CHF₂, CH₂CF₃, CF₂CF₃, C₁-C₆-alkyl, in particular C₂-C₆-alkyl, especially C₃-C₆-alkyl such as n-propyl, n-butyl, iso-butyl, n-pentyl, the aforementioned alkyl radical can be unsubstituted or carries one radical selected from the group consisting of C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular methoxy, ethoxy or OCF₃. In particular R^(a) is selected from the group consisting of ethyl, n-propyl, n-butyl, cyclopropyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2,2-trifluoroethyl and 2-trifluoromethoxyethyl. In a particular embodiment of the invention R^(a) is C₂-C₆-alkyl, especially C₂-C₄-alkyl which carries one radical selected from the group consisting of C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular methoxy, ethoxy or OCF₃, such as 2-methoxyethyl, 2-ethoxyethyl, 2,2,2-trifluoroethyl and 2-trifluoromethoxyethyl. In another particular embodiment R^(a) is a radical NR^(a3)R^(a4), where R^(a3) has one of the aforementioned meanings and is in particular selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(a4) has one of the aforementioned meanings and is in particular selected from elected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 10-membered, in particular 3- to 7-membered saturated heterocyclyl, 3- to 10-membered, in particular 3- to 7-membered saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R^(ac), where R^(ac) has one of the meanings given for R^(1c).

Where present, R^(a1) and R^(a2) are independently of each other in particular selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl. Especially, R^(a1) is selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(a2) is selected from hydrogen and C₁-C₄-alkyl.

Where present, R^(a3) is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl.

Where present, R^(a4) is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 10-membered, in particular 3- to 7-membered saturated heterocyclyl, 3- to 10-membered, in particular 3- to 7-membered saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R^(ac) where R^(ac) has one of the meanings given for R^(1c).

The radical R^(b) is hydrogen, halogen or C₁-C₄-alkyl, in particular hydrogen.

The radical Z is preferably selected from the group consisting of O, S or NR^(Z), in particular O and NR^(Z), especially O and NH.

If Z is a radical NR^(Z), R^(Z) is in particular selected from the group consisting of hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, which is unsubstituted or carries one radical selected from C₁-C₄-alkoxy and NR^(Z1)R^(Z2), SO₂R^(Z3) or a radical S(O)₂NR^(Z4)R^(Z5).

Where present, R^(Z1) and R^(Z2) are independently of each other in particular selected from the group consisting of hydrogen, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and C₁-C₄-alkoxy-C₁-C₄-alkyl. In particular, R^(Z1) and R^(Z2) may also form together with the nitrogen to which they are attached a 5- or 6-membered N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals, examples including 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidinyl or N-methylpiperazin-1-yl.

Where present, R^(Z3) is in particular selected from C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, phenyl or benzyl, wherein the phenyl ring in the last two mentioned itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy. Especially, R^(Z3), where present is C₁-C₄-alkyl such as methyl.

Where present, R^(Z4) and R^(Z5) have in particular one of the particular meanings given for R^(Z1) and R^(Z2).

Q is CH₂ or CH₂CH₂, in particular CH₂.

In a particular embodiment of the invention, X² is C—R², where R² is as defined above and R² is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy or a radical (CH₂)_(n)NR′R″, wherein n is 0 or 1. R′ and R″ have one of the meanings given for R^(Z1) and R^(Z2). Especially R² is hydrogen, i.e. X² is C—H. In this particular embodiment, X³ is C—R³ and X⁴ is C—R⁴ or one of X³ and X⁴ may also be N. In this embodiment, particular preference is given to compounds, wherein X³ is C—R³ and X⁴ is C—R⁴. Where occurring, R³ and R⁴ are as defined above, and in particular selected, independently of each other, from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy.

In a particular embodiment of the invention X² is N. If X² is N then X³ is C—R³ and X⁴ is C—R⁴, where R³ and R⁴ are as defined above and in particular selected, independently of each other, from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy.

X³ is in particular C—R³, where R³ is as defined above and wherein R³ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, bromine, methyl and methoxy.

X⁴ is in particular C—R⁴, where R⁴ is as defined above and wherein R⁴ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy.

A first particular embodiment of the invention relates to compounds according to formula I, their salts and N-oxides, where X², X³ and X⁴ are CR², CR³ and CR⁴, respectively, wherein R², R³ and R⁴ are as defined above. In this particular embodiment, R² is in particular hydrogen. In this particular embodiment, R³ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, bromine, methyl and methoxy. In this particular embodiment, R⁴ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy. Especially one or both of the radicals R³ and R⁴ are different from hydrogen while R² is hydrogen, with a particular preference given to compounds, wherein R³ is hydrogen and R⁴ is halogen such as chlorine.

In a second particular embodiment according to compounds of formula I, their salts and N-oxides X² is N while X³ and X⁴ are CR³ and CR⁴, respectively, wherein R³ and R⁴ are as defined above. In this particular embodiment, R³ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy. In this particular embodiment, R⁴ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy. Especially one or both of the radicals R³ and R⁴ are different from hydrogen, with a particular preference given to compounds, wherein R³ is hydrogen and R⁴ is halogen such as chlorine.

In a third embodiment according to compounds of formula I, their salts and N-oxides X³ is N and X² and X⁴ are CR² and CR⁴, respectively, wherein R² and R⁴ are as defined above. In this particular embodiment, R² is in particular hydrogen. In this particular embodiment, R⁴ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, methyl and methoxy.

A further embodiment of the invention relates to compounds of formula I, their salts and N-oxides, wherein X⁴ is N and X² and X³ are CR² and CR³, respectively, wherein R² and R³ are as defined above. In this particular embodiment, R² is in particular hydrogen. In this particular embodiment, R³ is in particular selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting of hydrogen, chlorine, bromine, methyl and methoxy.

Furthermore, one embodiment of the invention relates to compounds of formula I, their salts and N-oxides, wherein Z is bound to Y¹, i.e. Y¹ is C, Y² is C—R⁶, Y³ is C—R⁷ and Y⁴ is C—R⁸ or one of Y², Y³ or Y⁴ may also be N. Where occurring, R⁶, R⁷ and R⁸ are independently of each other selected from hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preference is given to those compounds, wherein Y² is C—R⁶, Y³ is C—R⁷ and Y⁴ is C—R⁸. In this particular embodiment, R⁶, R⁷ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I, their salts and N-oxides, wherein Z is bound to Y², i.e. Y² is C, Y¹ is C—R⁵, Y³ is C—R⁷ and Y⁴ is C—R⁸ or one of Y¹, Y³ or Y⁴ may also be N. Where occurring, R⁵, R⁷ and R⁸ are independently of each other preferably selected from hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preference is given to those compounds, wherein Y¹ is C—R⁵, Y³ is C—R⁷ and Y⁴ is C—R⁸. In this particular embodiment R⁵ is in particular hydrogen, chlorine, methyl, or methoxy, especially hydrogen. In this particular embodiment R⁷ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I, their salts and N-oxides, wherein Z is bound to Y³, i.e. Y³ is C, Y¹ is C—R⁵, Y² is C—R⁶ and Y⁴ is C—R⁸ or one of Y¹, Y³ or Y⁴ may also be N. Where occurring, R⁵, R⁶ and R⁸ are independently of each other preferably selected from hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preference is given to those compounds, wherein Y¹ is C—R⁵, Y² is C—R⁶ and Y⁴ is C—R⁸. In this particular embodiment, R⁵ is in particular hydrogen, chlorine, methyl, or methoxy, especially hydrogen. In this particular embodiment, R⁷ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I, their salts and N-oxides, wherein Z is bound to Y⁴, i.e. Y⁴ is C, Y¹ is C—R⁵, Y² is C—R⁶ and Y³ is C—R⁷ or one of Y¹, Y² or Y³ may also be N. Where occurring, R⁵, R⁶ and R⁷ are independently of each other preferably selected from hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preference is given to those compounds, wherein Y¹ is CR⁵, Y² is CR⁶ and Y³ is C—R⁷. In this particular embodiment, R⁵ is in particular hydrogen, chlorine, methyl, or methoxy, especially hydrogen. In this particular embodiment, R⁶ and R⁷ are especially hydrogen.

An especially preferred embodiment of the present invention relates to compounds of the formula I, to their salts and to the N-oxides, wherein X² is CH, X³ is C—R³ and X⁴ is C—R⁴, where the radicals R³ and R⁴ are as defined above and in particular selected from hydrogen, chlorine, methyl or methoxy. Especially one or both of the radicals R³ and R⁴ are different from hydrogen, with a particular preference given to compounds, wherein R³ is hydrogen and R⁴ is halogen, such as chlorine. Amongst these, particular preference is given to compounds, wherein Y¹ is C—R⁵, Y² is C, Y³ is C—R⁷ and Y⁴ is N or C—R⁸ or wherein Y¹ is C—R⁵, Y³ is C, Y² is C—R⁶ and Y⁴ is N or C—R⁸. In this especially preferred embodiment, Y⁴ is in particular C—R⁸. In this especially preferred embodiment, R⁵, R⁶, R⁷ and R⁸, where occurring, are as defined above. In this especial embodiment, R⁵ is in particular hydrogen, chlorine, methyl, or methoxy, especially hydrogen. In this especial embodiment, R⁶, R⁷ and R⁸ are especially hydrogen. In this especially preferred embodiment, R¹, Q, Z, R^(a) and R^(b) are as defined above and have in particular one of the preferred, particular or especially given meanings.

Another especially preferred embodiment of the present invention relates to compounds of the formula I, to their salts and to the N-oxides, wherein X² is N, X³ is C—R³ and X⁴ is C—R⁴, where the radicals R³ and R⁴ are as defined above and in particular selected from hydrogen, chlorine, methyl or methoxy. Especially one or both of the radicals R³ and R⁴ are different from hydrogen, with a particular preference given to compounds, wherein R³ is hydrogen and R⁴ is halogen, such as chlorine. Amongst these, particular preference is given to compounds, wherein Y¹ is C—R⁵, Y² is C, Y³ is C—R⁷ and Y⁴ is N or C—R⁸ or wherein Y¹ is C—R⁵, Y³ is C, Y² is C—R⁶ and Y⁴ is N or C—R⁸. In this especially preferred embodiment, Y⁴ is in particular C—R⁸. In this especially preferred embodiment, R⁵, R⁶, R⁷ and R⁸, where occurring, are as defined above. In this especial embodiment, R⁵ is in particular hydrogen, chlorine, methyl, or methoxy, especially hydrogen. In this especial embodiment, R⁶, R⁷ and R⁸ are especially hydrogen. In this especial embodiment, R^(b) is especially hydrogen. In this especially preferred embodiment, R¹, Q, Z, and R^(a) are as defined above and have in particular one of the preferred, particular or especially given meanings.

The compounds of the general formulae Ia and Ib, wherein Z, Q, R¹, R³, R⁴, R⁵ and R^(a) are as defined above and their pharmaceutically acceptable salts, represent per se especially preferred embodiments of the present invention.

Particular examples of compounds of the general formulae Ia and Ib are indicated in the Table 1-28 below. The meanings for R¹, R³, R⁴ and R⁵ indicated in Table A below represent embodiments of the invention which are likewise preferred independently of one another and especially in combination.

TABLE 1 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 2 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 3 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 4 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 5 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 6 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 7 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂ and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 8 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 9 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 10 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 11 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 12 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 13 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 14 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂ and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 15 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 16 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 17 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 18 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 19 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 20 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 21 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂CH₂ and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 22 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 23 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 24 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 25 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 26 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 27 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 28 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂CH₂ and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE A No. R¹ R³ R⁴ R⁵ A1 H H H H A2 CH₃ H H H A3 C₂H₅ H H H A4 n-C₃H₇ H H H A5 n-C₄H₉ H H H A6 n-C₅H₁₁ H H H A7 n-C₆H₁₃ H H H A8 CF₃ H H H A9 CH₂CF₃ H H H A10 OCH₃ H H H A11 OCH₂—CH₃ H H H A12 OCH₂—CH₂—CH₃ H H H A13 OCH₂—CH₂—CH₂—CH₃ H H H A14 OCF₃ H H H A15 OCHF₂ H H H A16 OCH₂—CF₃ H H H A17 Phenyl H H H A18 Phenoxy H H H A19 Benzyl H H H A20 Cl H H H A21 Br H H H A22 I H H H A23 NH₂ H H H A24 NH-Phenyl H H H A25 CN H H H A26 NH-Benzyl H H H A27 4-cyanophenyl H H H A28 1,4-oxazepan-4-yl H H H A29 4-Morpholinyl H H H A30 4-Methylpiperazin-1-yl H H H A31 N(2-methoxyethyl)(methyl) H H H A32 N(3-methoxypropyl)(methyl) H H H A33 H Cl H H A34 CH₃ Cl H H A35 C₂H₅ Cl H H A36 n-C₃H₇ Cl H H A37 n-C₄H₉ Cl H H A38 n-C₅H₁₁ Cl H H A39 n-C₆H₁₃ Cl H H A40 CF₃ Cl H H A41 CH₂CF₃ Cl H H A42 OCH₃ Cl H H A43 OCH₂—CH₃ Cl H H A44 OCH₂—CH₂—CH₃ Cl H H A45 OCH₂—CH₂—CH₂—CH₃ Cl H H A46 OCF₃ Cl H H A47 OCHF₂ Cl H H A48 OCH₂—CF₃ Cl H H A49 Phenyl Cl H H A50 Phenoxy Cl H H A51 Benzyl Cl H H A52 Cl Cl H H A53 Br Cl H H A54 I Cl H H A55 NH₂ Cl H H A56 NH-Phenyl Cl H H A57 CN Cl H H A58 NH-Benzyl Cl H H A59 4-cyanophenyl Cl H H A60 1,4-oxazepan-4-yl Cl H H A61 4-Morpholinyl Cl H H A62 4-Methylpiperazin-1-yl Cl H H A63 N(2-methoxyethyl)(methyl) Cl H H A64 N(3-methoxypropyl)(methyl) Cl H H A65 H H Cl H A66 CH₃ H Cl H A67 C₂H₅ H Cl H A68 n-C₃H₇ H Cl H A69 n-C₄H₉ H Cl H A70 n-C₅H₁₁ H Cl H A71 n-C₆H₁₃ H Cl H A72 CF₃ H Cl H A73 CH₂CF₃ H Cl H A74 OCH₃ H Cl H A75 OCH₂—CH₃ H Cl H A76 OCH₂—CH₂—CH₃ H Cl H A77 OCH₂—CH₂—CH₂—CH₃ H Cl H A78 OCF₃ H Cl H A79 OCHF₂ H Cl H A80 OCH₂—CF₃ H Cl H A81 Phenyl H Cl H A82 Phenoxy H Cl H A83 Benzyl H Cl H A84 Cl H Cl H A85 Br H Cl H A86 I H Cl H A87 NH₂ H Cl H A88 NH-Phenyl H Cl H A89 CN H Cl H A90 NH-Benzyl H Cl H A91 4-cyanophenyl H Cl H A92 1,4-oxazepan-4-yl H Cl H A93 4-Morpholinyl H Cl H A94 4-Methylpiperazin-1-yl H Cl H A95 N(2-methoxyethyl)(methyl) H Cl H A96 N(3-methoxypropyl)(methyl) H Cl H A97 H Br H H A98 CH₃ Br H H A99 C₂H₅ Br H H A100 n-C₃H₇ Br H H A101 n-C₄H₉ Br H H A102 n-C₅H₁₁ Br H H A103 n-C₆H₁₃ Br H H A104 CF₃ Br H H A105 CH₂CF₃ Br H H A106 OCH₃ Br H H A107 OCH₂—CH₃ Br H H A108 OCH₂—CH₂—CH₃ Br H H A109 OCH₂—CH₂—CH₂—CH₃ Br H H A110 OCF₃ Br H H A111 OCHF₂ Br H H A112 OCH₂—CF₃ Br H H A113 Phenyl Br H H A114 Phenoxy Br H H A115 Benzyl Br H H A116 Cl Br H H A117 Br Br H H A118 I Br H H A119 NH₂ Br H H A120 NH-Phenyl Br H H A121 CN Br H H A122 NH-Benzyl Br H H A123 4-cyanophenyl Br H H A124 1,4-oxazepan-4-yl Br H H A125 4-Morpholinyl Br H H A126 4-Methylpiperazin-1-yl Br H H A127 N(2-methoxyethyl)(methyl) Br H H A128 N(3-methoxypropyl)(methyl) Br H H A129 H H Br H A130 CH₃ H Br H A131 C₂H₅ H Br H A132 n-C₃H₇ H Br H A133 n-C₄H₉ H Br H A134 n-C₅H₁₁ H Br H A135 n-C₆H₁₃ H Br H A136 CF₃ H Br H A137 CH₂CF₃ H Br H A138 OCH₃ H Br H A139 OCH₂—CH₃ H Br H A140 OCH₂—CH₂—CH₃ H Br H A141 OCH₂—CH₂—CH₂—CH₃ H Br H A142 OCF₃ H Br H A143 OCHF₂ H Br H A144 OCH₂—CF₃ H Br H A145 Phenyl H Br H A146 Phenoxy H Br H A147 Benzyl H Br H A148 Cl H Br H A149 Br H Br H A150 I H Br H A151 NH₂ H Br H A152 NH-Phenyl H Br H A153 CN H Br H A154 NH-Benzyl H Br H A155 4-cyanophenyl H Br H A156 1,4-oxazepan-4-yl H Br H A157 4-Morpholinyl H Br H A158 4-Methylpiperazin-1-yl H Br H A159 N(2-methoxyethyl)(methyl) H Br H A160 N(3-methoxypropyl)(methyl) H Br H A161 H CH₃ H H A162 CH₃ CH₃ H H A163 C₂H₅ CH₃ H H A164 n-C₃H₇ CH₃ H H A165 n-C₄H₉ CH₃ H H A166 n-C₅H₁₁ CH₃ H H A167 n-C₆H₁₃ CH₃ H H A168 CF₃ CH₃ H H A169 CH₂CF₃ CH₃ H H A170 OCH₃ CH₃ H H A171 OCH₂—CH₃ CH₃ H H A172 OCH₂—CH₂—CH₃ CH₃ H H A173 OCH₂—CH₂—CH₂—CH₃ CH₃ H H A174 OCF₃ CH₃ H H A175 OCHF₂ CH₃ H H A176 OCH₂—CF₃ CH₃ H H A177 Phenyl CH₃ H H A178 Phenoxy CH₃ H H A179 Benzyl CH₃ H H A180 Cl CH₃ H H A181 Br CH₃ H H A182 I CH₃ H H A183 NH₂ CH₃ H H A184 NH-Phenyl CH₃ H H A185 CN CH₃ H H A186 NH-Benzyl CH₃ H H A187 4-cyanophenyl CH₃ H H A188 1,4-oxazepan-4-yl CH₃ H H A189 4-Morpholinyl CH₃ H H A190 4-Methylpiperazin-1-yl CH₃ H H A191 N(2-methoxyethyl)(methyl) CH₃ H H A192 N(3-methoxypropyl)(methyl) CH₃ H H A193 H H CH₃ H A194 CH₃ H CH₃ H A195 C₂H₅ H CH₃ H A196 n-C₃H₇ H CH₃ H A197 n-C₄H₉ H CH₃ H A198 n-C₅H₁₁ H CH₃ H A199 n-C₆H₁₃ H CH₃ H A200 CF₃ H CH₃ H A201 CH₂CF₃ H CH₃ H A202 OCH₃ H CH₃ H A203 OCH₂—CH₃ H CH₃ H A204 OCH₂—CH₂—CH₃ H CH₃ H A205 OCH₂—CH₂—CH₂—CH₃ H CH₃ H A206 OCF₃ H CH₃ H A207 OCHF₂ H CH₃ H A208 OCH₂—CF₃ H CH₃ H A209 Phenyl H CH₃ H A210 Phenoxy H CH₃ H A211 Benzyl H CH₃ H A212 Cl H CH₃ H A213 Br H CH₃ H A214 I H CH₃ H A215 NH₂ H CH₃ H A216 NH-Phenyl H CH₃ H A217 CN H CH₃ H A218 NH-Benzyl H CH₃ H A219 4-cyanophenyl H CH₃ H A220 1,4-oxazepan-4-yl H CH₃ H A221 4-Morpholinyl H CH₃ H A222 4-Methylpiperazin-1-yl H CH₃ H A223 N(2-methoxyethyl)(methyl) H CH₃ H A224 N(3-methoxypropyl)(methyl) H CH₃ H A225 H CH₃ CH₃ H A226 CH₃ CH₃ CH₃ H A227 C₂H₅ CH₃ CH₃ H A228 n-C₃H₇ CH₃ CH₃ H A229 n-C₄H₉ CH₃ CH₃ H A230 n-C₅H₁₁ CH₃ CH₃ H A231 n-C₆H₁₃ CH₃ CH₃ H A232 CF₃ CH₃ CH₃ H A233 CH₂CF₃ CH₃ CH₃ H A234 OCH₃ CH₃ CH₃ H A235 OCH₂—CH₃ CH₃ CH₃ H A236 OCH₂—CH₂—CH₃ CH₃ CH₃ H A237 OCH₂—CH₂—CH₂—CH₃ CH₃ CH₃ H A238 OCF₃ CH₃ CH₃ H A239 OCHF₂ CH₃ CH₃ H A240 OCH₂—CF₃ CH₃ CH₃ H A241 Phenyl CH₃ CH₃ H A242 Phenoxy CH₃ CH₃ H A243 Benzyl CH₃ CH₃ H A244 Cl CH₃ CH₃ H A245 Br CH₃ CH₃ H A246 I CH₃ CH₃ H A247 NH₂ CH₃ CH₃ H A248 NH-Phenyl CH₃ CH₃ H A249 CN CH₃ CH₃ H A250 NH-Benzyl CH₃ CH₃ H A251 4-cyanophenyl CH₃ CH₃ H A252 1,4-oxazepan-4-yl CH₃ CH₃ H A253 4-Morpholinyl CH₃ CH₃ H A254 4-Methylpiperazin-1-yl CH₃ CH₃ H A255 N(2-methoxyethyl)(methyl) CH₃ CH₃ H A256 N(3-methoxypropyl)(methyl) CH₃ CH₃ H A257 H C₂H₅ C₂H₅ H A258 CH₃ C₂H₅ C₂H₅ H A259 C₂H₅ C₂H₅ C₂H₅ H A260 n-C₃H₇ C₂H₅ C₂H₅ H A261 n-C₄H₉ C₂H₅ C₂H₅ H A262 n-C₅H₁₁ C₂H₅ C₂H₅ H A263 n-C₆H₁₃ C₂H₅ C₂H₅ H A264 CF₃ C₂H₅ C₂H₅ H A265 CH₂CF₃ C₂H₅ C₂H₅ H A266 OCH₃ C₂H₅ C₂H₅ H A267 OCH₂—CH₃ C₂H₅ C₂H₅ H A268 OCH₂—CH₂—CH₃ C₂H₅ C₂H₅ H A269 OCH₂—CH₂—CH₂—CH₃ C₂H₅ C₂H₅ H A270 OCF₃ C₂H₅ C₂H₅ H A271 OCHF₂ C₂H₅ C₂H₅ H A272 OCH₂—CF₃ C₂H₅ C₂H₅ H A273 Phenyl C₂H₅ C₂H₅ H A274 Phenoxy C₂H₅ C₂H₅ H A275 Benzyl C₂H₅ C₂H₅ H A276 Cl C₂H₅ C₂H₅ H A277 Br C₂H₅ C₂H₅ H A278 I C₂H₅ C₂H₅ H A279 NH₂ C₂H₅ C₂H₅ H A280 NH-Phenyl C₂H₅ C₂H₅ H A281 CN C₂H₅ C₂H₅ H A282 NH-Benzyl C₂H₅ C₂H₅ H A283 4-cyanophenyl C₂H₅ C₂H₅ H A284 1,4-oxazepan-4-yl C₂H₅ C₂H₅ H A285 4-Morpholinyl C₂H₅ C₂H₅ H A286 4-Methylpiperazin-1-yl C₂H₅ C₂H₅ H A287 N(2-methoxyethyl)(methyl) C₂H₅ C₂H₅ H A288 N(3-methoxypropyl)(methyl) C₂H₅ C₂H₅ H A289 H CH₃O H H A290 CH₃ CH₃O H H A291 C₂H₅ CH₃O H H A292 n-C₃H₇ CH₃O H H A293 n-C₄H₉ CH₃O H H A294 n-C₅H₁₁ CH₃O H H A295 n-C₆H₁₃ CH₃O H H A296 CF₃ CH₃O H H A297 CH₂CF₃ CH₃O H H A298 OCH₃ CH₃O H H A299 OCH₂—CH₃ CH₃O H H A300 OCH₂—CH₂—CH₃ CH₃O H H A301 OCH₂—CH₂—CH₂—CH₃ CH₃O H H A302 OCF₃ CH₃O H H A303 OCHF₂ CH₃O H H A304 OCH₂—CF₃ CH₃O H H A305 Phenyl CH₃O H H A306 Phenoxy CH₃O H H A307 Benzyl CH₃O H H A308 Cl CH₃O H H A309 Br CH₃O H H A310 I CH₃O H H A311 NH₂ CH₃O H H A312 NH-Phenyl CH₃O H H A313 CN CH₃O H H A314 NH-Benzyl CH₃O H H A315 4-cyanophenyl CH₃O H H A316 1,4-oxazepan-4-yl CH₃O H H A317 4-Morpholinyl CH₃O H H A318 4-Methylpiperazin-1-yl CH₃O H H A319 N(2-methoxyethyl)(methyl) CH₃O H H A320 N(3-methoxypropyl)(methyl) CH₃O H H A321 H H CH₃O H A322 CH₃ H CH₃O H A323 C₂H₅ H CH₃O H A324 n-C₃H₇ H CH₃O H A325 n-C₄H₉ H CH₃O H A326 n-C₅H₁₁ H CH₃O H A327 n-C₆H₁₃ H CH₃O H A328 CF₃ H CH₃O H A329 CH₂CF₃ H CH₃O H A330 OCH₃ H CH₃O H A331 OCH₂—CH₃ H CH₃O H A332 OCH₂—CH₂—CH₃ H CH₃O H A333 OCH₂—CH₂—CH₂—CH₃ H CH₃O H A334 OCF₃ H CH₃O H A335 OCHF₂ H CH₃O H A336 OCH₂—CF₃ H CH₃O H A337 Phenyl H CH₃O H A338 Phenoxy H CH₃O H A339 Benzyl H CH₃O H A340 Cl H CH₃O H A341 Br H CH₃O H A342 I H CH₃O H A343 NH₂ H CH₃O H A344 NH-Phenyl H CH₃O H A345 CN H CH₃O H A346 NH-Benzyl H CH₃O H A347 4-cyanophenyl H CH₃O H A348 1,4-oxazepan-4-yl H CH₃O H A349 4-Morpholinyl H CH₃O H A350 4-Methylpiperazin-1-yl H CH₃O H A351 N(2-methoxyethyl)(methyl) H CH₃O H A352 N(3-methoxypropyl)(methyl) H CH₃O H A353 H H H CH₃ A354 CH₃ H H CH₃ A355 C₂H₅ H H CH₃ A356 n-C₃H₇ H H CH₃ A357 n-C₄H₉ H H CH₃ A358 n-C₅H₁₁ H H CH₃ A359 n-C₆H₁₃ H H CH₃ A360 CF₃ H H CH₃ A361 CH₂CF₃ H H CH₃ A362 OCH₃ H H CH₃ A363 OCH₂—CH₃ H H CH₃ A364 OCH₂—CH₂—CH₃ H H CH₃ A365 OCH₂—CH₂—CH₂—CH₃ H H CH₃ A366 OCF₃ H H CH₃ A367 OCHF₂ H H CH₃ A368 OCH₂—CF₃ H H CH₃ A369 Phenyl H H CH₃ A370 Phenoxy H H CH₃ A371 Benzyl H H CH₃ A372 Cl H H CH₃ A373 Br H H CH₃ A374 I H H CH₃ A375 NH₂ H H CH₃ A376 NH-Phenyl H H CH₃ A377 CN H H CH₃ A378 NH-Benzyl H H CH₃ A379 4-cyanophenyl H H CH₃ A380 1,4-oxazepan-4-yl H H CH₃ A381 4-Morpholinyl H H CH₃ A382 4-Methylpiperazin-1-yl H H CH₃ A383 N(2-methoxyethyl)(methyl) H H CH₃ A384 N(3-methoxypropyl)(methyl) H H CH₃ A385 H Cl H CH₃ A386 CH₃ Cl H CH₃ A387 C₂H₅ Cl H CH₃ A388 n-C₃H₇ Cl H CH₃ A389 n-C₄H₉ Cl H CH₃ A390 n-C₅H₁₁ Cl H CH₃ A391 n-C₆H₁₃ Cl H CH₃ A392 CF₃ Cl H CH₃ A393 CH₂CF₃ Cl H CH₃ A394 OCH₃ Cl H CH₃ A395 OCH₂—CH₃ Cl H CH₃ A396 OCH₂—CH₂—CH₃ Cl H CH₃ A397 OCH₂—CH₂—CH₂—CH₃ Cl H CH₃ A398 OCF₃ Cl H CH₃ A399 OCHF₂ Cl H CH₃ A400 OCH₂—CF₃ Cl H CH₃ A401 Phenyl Cl H CH₃ A402 Phenoxy Cl H CH₃ A403 Benzyl Cl H CH₃ A404 Cl Cl H CH₃ A405 Br Cl H CH₃ A406 I Cl H CH₃ A407 NH₂ Cl H CH₃ A408 NH-Phenyl Cl H CH₃ A409 CN Cl H CH₃ A410 NH-Benzyl Cl H CH₃ A411 4-cyanophenyl Cl H CH₃ A412 1,4-oxazepan-4-yl Cl H CH₃ A413 4-Morpholinyl Cl H CH₃ A414 4-Methylpiperazin-1-yl Cl H CH₃ A415 N(2-methoxyethyl)(methyl) Cl H CH₃ A416 N(3-methoxypropyl)(methyl) Cl H CH₃ A417 H H Cl CH₃ A418 CH₃ H Cl CH₃ A419 C₂H₅ H Cl CH₃ A420 n-C₃H₇ H Cl CH₃ A421 n-C₄H₉ H Cl CH₃ A422 n-C₅H₁₁ H Cl CH₃ A423 n-C₆H₁₃ H Cl CH₃ A424 CF₃ H Cl CH₃ A425 CH₂CF₃ H Cl CH₃ A426 OCH₃ H Cl CH₃ A427 OCH₂—CH₃ H Cl CH₃ A428 OCH₂—CH₂—CH₃ H Cl CH₃ A429 OCH₂—CH₂—CH₂—CH₃ H Cl CH₃ A430 OCF₃ H Cl CH₃ A431 OCHF₂ H Cl CH₃ A432 OCH₂—CF₃ H Cl CH₃ A433 Phenyl H Cl CH₃ A434 Phenoxy H Cl CH₃ A435 Benzyl H Cl CH₃ A436 Cl H Cl CH₃ A437 Br H Cl CH₃ A438 I H Cl CH₃ A439 NH₂ H Cl CH₃ A440 NH-Phenyl H Cl CH₃ A441 CN H Cl CH₃ A442 NH-Benzyl H Cl CH₃ A443 4-cyanophenyl H Cl CH₃ A444 1,4-oxazepan-4-yl H Cl CH₃ A445 4-Morpholinyl H Cl CH₃ A446 4-Methylpiperazin-1-yl H Cl CH₃ A447 N(2-methoxyethyl)(methyl) H Cl CH₃ A448 N(3-methoxypropyl)(methyl) H Cl CH₃ A449 H Br H CH₃ A450 CH₃ Br H CH₃ A451 C₂H₅ Br H CH₃ A452 n-C₃H₇ Br H CH₃ A453 n-C₄H₉ Br H CH₃ A454 n-C₅H₁₁ Br H CH₃ A455 n-C₆H₁₃ Br H CH₃ A456 CF₃ Br H CH₃ A457 CH₂CF₃ Br H CH₃ A458 OCH₃ Br H CH₃ A459 OCH₂—CH₃ Br H CH₃ A460 OCH₂—CH₂—CH₃ Br H CH₃ A461 OCH₂—CH₂—CH₂—CH₃ Br H CH₃ A462 OCF₃ Br H CH₃ A463 OCHF₂ Br H CH₃ A464 OCH₂—CF₃ Br H CH₃ A465 Phenyl Br H CH₃ A466 Phenoxy Br H CH₃ A467 Benzyl Br H CH₃ A468 Cl Br H CH₃ A469 Br Br H CH₃ A470 I Br H CH₃ A471 NH₂ Br H CH₃ A472 NH-Phenyl Br H CH₃ A473 CN Br H CH₃ A474 NH-Benzyl Br H CH₃ A475 4-cyanophenyl Br H CH₃ A476 1,4-oxazepan-4-yl Br H CH₃ A477 4-Morpholinyl Br H CH₃ A478 4-Methylpiperazin-1-yl Br H CH₃ A479 N(2-methoxyethyl)(methyl) Br H CH₃ A480 N(3-methoxypropyl)(methyl) Br H CH₃ A481 H H Br CH₃ A482 CH₃ H Br CH₃ A483 C₂H₅ H Br CH₃ A484 n-C₃H₇ H Br CH₃ A485 n-C₄H₉ H Br CH₃ A486 n-C₅H₁₁ H Br CH₃ A487 n-C₆H₁₃ H Br CH₃ A488 CF₃ H Br CH₃ A489 CH₂CF₃ H Br CH₃ A490 OCH₃ H Br CH₃ A491 OCH₂—CH₃ H Br CH₃ A492 OCH₂—CH₂—CH₃ H Br CH₃ A493 OCH₂—CH₂—CH₂—CH₃ H Br CH₃ A494 OCF₃ H Br CH₃ A495 OCHF₂ H Br CH₃ A496 OCH₂—CF₃ H Br CH₃ A497 Phenyl H Br CH₃ A498 Phenoxy H Br CH₃ A499 Benzyl H Br CH₃ A500 Cl H Br CH₃ A501 Br H Br CH₃ A502 I H Br CH₃ A503 NH₂ H Br CH₃ A504 NH-Phenyl H Br CH₃ A505 CN H Br CH₃ A506 NH-Benzyl H Br CH₃ A507 4-cyanophenyl H Br CH₃ A508 1,4-oxazepan-4-yl H Br CH₃ A509 4-Morpholinyl H Br CH₃ A510 4-Methylpiperazin-1-yl H Br CH₃ A511 N(2-methoxyethyl)(methyl) H Br CH₃ A512 N(3-methoxypropyl)(methyl) H Br CH₃ A513 H CH₃ H CH₃ A514 CH₃ CH₃ H CH₃ A515 C₂H₅ CH₃ H CH₃ A516 n-C₃H₇ CH₃ H CH₃ A517 n-C₄H₉ CH₃ H CH₃ A518 n-C₅H₁₁ CH₃ H CH₃ A519 n-C₆H₁₃ CH₃ H CH₃ A520 CF₃ CH₃ H CH₃ A521 CH₂CF₃ CH₃ H CH₃ A522 OCH₃ CH₃ H CH₃ A523 OCH₂—CH₃ CH₃ H CH₃ A524 OCH₂—CH₂—CH₃ CH₃ H CH₃ A525 OCH₂—CH₂—CH₂—CH₃ CH₃ H CH₃ A526 OCF₃ CH₃ H CH₃ A527 OCHF₂ CH₃ H CH₃ A528 OCH₂—CF₃ CH₃ H CH₃ A529 Phenyl CH₃ H CH₃ A530 Phenoxy CH₃ H CH₃ A531 Benzyl CH₃ H CH₃ A532 Cl CH₃ H CH₃ A533 Br CH₃ H CH₃ A534 I CH₃ H CH₃ A535 NH₂ CH₃ H CH₃ A536 NH-Phenyl CH₃ H CH₃ A537 CN CH₃ H CH₃ A538 NH-Benzyl CH₃ H CH₃ A539 4-cyanophenyl CH₃ H CH₃ A540 1,4-oxazepan-4-yl CH₃ H CH₃ A541 4-Morpholinyl CH₃ H CH₃ A542 4-Methylpiperazin-1-yl CH₃ H CH₃ A543 N(2-methoxyethyl)(methyl) CH₃ H CH₃ A544 N(3-methoxypropyl)(methyl) CH₃ H CH₃ A545 H H CH₃ CH₃ A546 CH₃ H CH₃ CH₃ A547 C₂H₅ H CH₃ CH₃ A548 n-C₃H₇ H CH₃ CH₃ A549 n-C₄H₉ H CH₃ CH₃ A550 n-C₅H₁₁ H CH₃ CH₃ A551 n-C₆H₁₃ H CH₃ CH₃ A552 CF₃ H CH₃ CH₃ A553 CH₂CF₃ H CH₃ CH₃ A554 OCH₃ H CH₃ CH₃ A555 OCH₂—CH₃ H CH₃ CH₃ A556 OCH₂—CH₂—CH₃ H CH₃ CH₃ A557 OCH₂—CH₂—CH₂—CH₃ H CH₃ CH₃ A558 OCF₃ H CH₃ CH₃ A559 OCHF₂ H CH₃ CH₃ A560 OCH₂—CF₃ H CH₃ CH₃ A561 Phenyl H CH₃ CH₃ A562 Phenoxy H CH₃ CH₃ A563 Benzyl H CH₃ CH₃ A564 Cl H CH₃ CH₃ A565 Br H CH₃ CH₃ A566 I H CH₃ CH₃ A567 NH₂ H CH₃ CH₃ A568 NH-Phenyl H CH₃ CH₃ A569 CN H CH₃ CH₃ A570 NH-Benzyl H CH₃ CH₃ A571 4-cyanophenyl H CH₃ CH₃ A572 1,4-oxazepan-4-yl H CH₃ CH₃ A573 4-Morpholinyl H CH₃ CH₃ A574 4-Methylpiperazin-1-yl H CH₃ CH₃ A575 N(2-methoxyethyl)(methyl) H CH₃ CH₃ A576 N(3-methoxypropyl)(methyl) H CH₃ CH₃ A577 H CH₃ CH₃ CH₃ A578 CH₃ CH₃ CH₃ CH₃ A579 C₂H₅ CH₃ CH₃ CH₃ A580 n-C₃H₇ CH₃ CH₃ CH₃ A581 n-C₄H₉ CH₃ CH₃ CH₃ A582 n-C₅H₁₁ CH₃ CH₃ CH₃ A583 n-C₆H₁₃ CH₃ CH₃ CH₃ A584 CF₃ CH₃ CH₃ CH₃ A585 CH₂CF₃ CH₃ CH₃ CH₃ A586 OCH₃ CH₃ CH₃ CH₃ A587 OCH₂—CH₃ CH₃ CH₃ CH₃ A588 OCH₂—CH₂—CH₃ CH₃ CH₃ CH₃ A589 OCH₂—CH₂—CH₂—CH₃ CH₃ CH₃ CH₃ A590 OCF₃ CH₃ CH₃ CH₃ A591 OCHF₂ CH₃ CH₃ CH₃ A592 OCH₂—CF₃ CH₃ CH₃ CH₃ A593 Phenyl CH₃ CH₃ CH₃ A594 Phenoxy CH₃ CH₃ CH₃ A595 Benzyl CH₃ CH₃ CH₃ A596 Cl CH₃ CH₃ CH₃ A597 Br CH₃ CH₃ CH₃ A598 I CH₃ CH₃ CH₃ A599 NH₂ CH₃ CH₃ CH₃ A600 NH-Phenyl CH₃ CH₃ CH₃ A601 CN CH₃ CH₃ CH₃ A602 NH-Benzyl CH₃ CH₃ CH₃ A603 4-cyanophenyl CH₃ CH₃ CH₃ A604 1,4-oxazepan-4-yl CH₃ CH₃ CH₃ A605 4-Morpholinyl CH₃ CH₃ CH₃ A606 4-Methylpiperazin-1-yl CH₃ CH₃ CH₃ A607 N(2-methoxyethyl)(methyl) CH₃ CH₃ CH₃ A608 N(3-methoxypropyl)(methyl) CH₃ CH₃ CH₃ A609 H C₂H₅ C₂H₅ CH₃ A610 CH₃ C₂H₅ C₂H₅ CH₃ A611 C₂H₅ C₂H₅ C₂H₅ CH₃ A612 n-C₃H₇ C₂H₅ C₂H₅ CH₃ A613 n-C₄H₉ C₂H₅ C₂H₅ CH₃ A614 n-C₅H₁₁ C₂H₅ C₂H₅ CH₃ A615 n-C₆H₁₃ C₂H₅ C₂H₅ CH₃ A616 CF₃ C₂H₅ C₂H₅ CH₃ A617 CH₂CF₃ C₂H₅ C₂H₅ CH₃ A618 OCH₃ C₂H₅ C₂H₅ CH₃ A619 OCH₂—CH₃ C₂H₅ C₂H₅ CH₃ A620 OCH₂—CH₂—CH₃ C₂H₅ C₂H₅ CH₃ A621 OCH₂—CH₂—CH₂—CH₃ C₂H₅ C₂H₅ CH₃ A622 OCF₃ C₂H₅ C₂H₅ CH₃ A623 OCHF₂ C₂H₅ C₂H₅ CH₃ A624 OCH₂—CF₃ C₂H₅ C₂H₅ CH₃ A625 Phenyl C₂H₅ C₂H₅ CH₃ A626 Phenoxy C₂H₅ C₂H₅ CH₃ A627 Benzyl C₂H₅ C₂H₅ CH₃ A628 Cl C₂H₅ C₂H₅ CH₃ A629 Br C₂H₅ C₂H₅ CH₃ A630 I C₂H₅ C₂H₅ CH₃ A631 NH₂ C₂H₅ C₂H₅ CH₃ A632 NH-Phenyl C₂H₅ C₂H₅ CH₃ A633 CN C₂H₅ C₂H₅ CH₃ A634 NH-Benzyl C₂H₅ C₂H₅ CH₃ A635 4-cyanophenyl C₂H₅ C₂H₅ CH₃ A636 1,4-oxazepan-4-yl C₂H₅ C₂H₅ CH₃ A637 4-Morpholinyl C₂H₅ C₂H₅ CH₃ A638 4-Methylpiperazin-1-yl C₂H₅ C₂H₅ CH₃ A639 N(2-methoxyethyl)(methyl) C₂H₅ C₂H₅ CH₃ A640 N(3-methoxypropyl)(methyl) C₂H₅ C₂H₅ CH₃ A641 H CH₃O H CH₃ A642 CH₃ CH₃O H CH₃ A643 C₂H₅ CH₃O H CH₃ A644 n-C₃H₇ CH₃O H CH₃ A645 n-C₄H₉ CH₃O H CH₃ A646 n-C₅H₁₁ CH₃O H CH₃ A647 n-C₆H₁₃ CH₃O H CH₃ A648 CF₃ CH₃O H CH₃ A649 CH₂CF₃ CH₃O H CH₃ A650 OCH₃ CH₃O H CH₃ A651 OCH₂—CH₃ CH₃O H CH₃ A652 OCH₂—CH₂—CH₃ CH₃O H CH₃ A653 OCH₂—CH₂—CH₂—CH₃ CH₃O H CH₃ A654 OCF₃ CH₃O H CH₃ A655 OCHF₂ CH₃O H CH₃ A656 OCH₂—CF₃ CH₃O H CH₃ A657 Phenyl CH₃O H CH₃ A658 Phenoxy CH₃O H CH₃ A659 Benzyl CH₃O H CH₃ A660 Cl CH₃O H CH₃ A661 Br CH₃O H CH₃ A662 I CH₃O H CH₃ A663 NH₂ CH₃O H CH₃ A664 NH-Phenyl CH₃O H CH₃ A665 CN CH₃O H CH₃ A666 NH-Benzyl CH₃O H CH₃ A667 4-cyanophenyl CH₃O H CH₃ A668 1,4-oxazepan-4-yl CH₃O H CH₃ A669 4-Morpholinyl CH₃O H CH₃ A670 4-Methylpiperazin-1-yl CH₃O H CH₃ A671 N(2-methoxyethyl)(methyl) CH₃O H CH₃ A672 N(3-methoxypropyl)(methyl) CH₃O H CH₃ A673 H H CH₃O CH₃ A674 CH₃ H CH₃O CH₃ A675 C₂H₅ H CH₃O CH₃ A676 n-C₃H₇ H CH₃O CH₃ A677 n-C₄H₉ H CH₃O CH₃ A678 n-C₅H₁₁ H CH₃O CH₃ A679 n-C₆H₁₃ H CH₃O CH₃ A680 CF₃ H CH₃O CH₃ A681 CH₂CF₃ H CH₃O CH₃ A682 OCH₃ H CH₃O CH₃ A683 OCH₂—CH₃ H CH₃O CH₃ A684 OCH₂—CH₂—CH₃ H CH₃O CH₃ A685 OCH₂—CH₂—CH₂—CH₃ H CH₃O CH₃ A686 OCF₃ H CH₃O CH₃ A687 OCHF₂ H CH₃O CH₃ A688 OCH₂—CF₃ H CH₃O CH₃ A689 Phenyl H CH₃O CH₃ A690 Phenoxy H CH₃O CH₃ A691 Benzyl H CH₃O CH₃ A692 Cl H CH₃O CH₃ A693 Br H CH₃O CH₃ A694 I H CH₃O CH₃ A695 NH₂ H CH₃O CH₃ A696 NH-Phenyl H CH₃O CH₃ A697 CN H CH₃O CH₃ A698 NH-Benzyl H CH₃O CH₃ A699 4-cyanophenyl H CH₃O CH₃ A700 1,4-oxazepan-4-yl H CH₃O CH₃ A701 4-Morpholinyl H CH₃O CH₃ A702 4-Methylpiperazin-1-yl H CH₃O CH₃ A703 N(2-methoxyethyl)(methyl) H CH₃O CH₃ A704 N(3-methoxypropyl)(methyl) H CH₃O CH₃ A705 H H H Cl A706 CH₃ H H Cl A707 C₂H₅ H H Cl A708 n-C₃H₇ H H Cl A709 n-C₄H₉ H H Cl A710 n-C₅H₁₁ H H Cl A711 n-C₆H₁₃ H H Cl A712 CF₃ H H Cl A713 CH₂CF₃ H H Cl A714 OCH₃ H H Cl A715 OCH₂—CH₃ H H Cl A716 OCH₂—CH₂—CH₃ H H Cl A717 OCH₂—CH₂—CH₂—CH₃ H H Cl A718 OCF₃ H H Cl A719 OCHF₂ H H Cl A720 OCH₂—CF₃ H H Cl A721 Phenyl H H Cl A722 Phenoxy H H Cl A723 Benzyl H H Cl A724 Cl H H Cl A725 Br H H Cl A726 I H H Cl A727 NH₂ H H Cl A728 NH-Phenyl H H Cl A729 CN H H Cl A730 NH-Benzyl H H Cl A731 4-cyanophenyl H H Cl A732 1,4-oxazepan-4-yl H H Cl A733 4-Morpholinyl H H Cl A734 4-Methylpiperazin-1-yl H H Cl A735 N(2-methoxyethyl)(methyl) H H Cl A736 N(3-methoxypropyl)(methyl) H H Cl A737 H Cl H Cl A738 CH₃ Cl H Cl A739 C₂H₅ Cl H Cl A740 n-C₃H₇ Cl H Cl A741 n-C₄H₉ Cl H Cl A742 n-C₅H₁₁ Cl H Cl A743 n-C₆H₁₃ Cl H Cl A744 CF₃ Cl H Cl A745 CH₂CF₃ Cl H Cl A746 OCH₃ Cl H Cl A747 OCH₂—CH₃ Cl H Cl A748 OCH₂—CH₂—CH₃ Cl H Cl A749 OCH₂—CH₂—CH₂—CH₃ Cl H Cl A750 OCF₃ Cl H Cl A751 OCHF₂ Cl H Cl A752 OCH₂—CF₃ Cl H Cl A753 Phenyl Cl H Cl A754 Phenoxy Cl H Cl A755 Benzyl Cl H Cl A756 Cl Cl H Cl A757 Br Cl H Cl A758 I Cl H Cl A759 NH₂ Cl H Cl A760 NH-Phenyl Cl H Cl A761 CN Cl H Cl A762 NH-Benzyl Cl H Cl A763 4-cyanophenyl Cl H Cl A764 1,4-oxazepan-4-yl Cl H Cl A765 4-Morpholinyl Cl H Cl A766 4-Methylpiperazin-1-yl Cl H Cl A767 N(2-methoxyethyl)(methyl) Cl H Cl A768 N(3-methoxypropyl)(methyl) Cl H Cl A769 H H Cl Cl A770 CH₃ H Cl Cl A771 C₂H₅ H Cl Cl A772 n-C₃H₇ H Cl Cl A773 n-C₄H₉ H Cl Cl A774 n-C₅H₁₁ H Cl Cl A775 n-C₆H₁₃ H Cl Cl A776 CF₃ H Cl Cl A777 CH₂CF₃ H Cl Cl A778 OCH₃ H Cl Cl A779 OCH₂—CH₃ H Cl Cl A780 OCH₂—CH₂—CH₃ H Cl Cl A781 OCH₂—CH₂—CH₂—CH₃ H Cl Cl A782 OCF₃ H Cl Cl A783 OCHF₂ H Cl Cl A784 OCH₂—CF₃ H Cl Cl A785 Phenyl H Cl Cl A786 Phenoxy H Cl Cl A787 Benzyl H Cl Cl A788 Cl H Cl Cl A789 Br H Cl Cl A790 I H Cl Cl A791 NH₂ H Cl Cl A792 NH-Phenyl H Cl Cl A793 CN H Cl Cl A794 NH-Benzyl H Cl Cl A795 4-cyanophenyl H Cl Cl A796 1,4-oxazepan-4-yl H Cl Cl A797 4-Morpholinyl H Cl Cl A798 4-Methylpiperazin-1-yl H Cl Cl A799 N(2-methoxyethyl)(methyl) H Cl Cl A800 N(3-methoxypropyl)(methyl) H Cl Cl A801 H Br H Cl A802 CH₃ Br H Cl A803 C₂H₅ Br H Cl A804 n-C₃H₇ Br H Cl A805 n-C₄H₉ Br H Cl A806 n-C₅H₁₁ Br H Cl A807 n-C₆H₁₃ Br H Cl A808 CF₃ Br H Cl A809 CH₂CF₃ Br H Cl A810 OCH₃ Br H Cl A811 OCH₂—CH₃ Br H Cl A812 OCH₂—CH₂—CH₃ Br H Cl A813 OCH₂—CH₂—CH₂—CH₃ Br H Cl A814 OCF₃ Br H Cl A815 OCHF₂ Br H Cl A816 OCH₂—CF₃ Br H Cl A817 Phenyl Br H Cl A818 Phenoxy Br H Cl A819 Benzyl Br H Cl A820 Cl Br H Cl A821 Br Br H Cl A822 I Br H Cl A823 NH₂ Br H Cl A824 NH-Phenyl Br H Cl A825 CN Br H Cl A826 NH-Benzyl Br H Cl A827 4-cyanophenyl Br H Cl A828 1,4-oxazepan-4-yl Br H Cl A829 4-Morpholinyl Br H Cl A830 4-Methylpiperazin-1-yl Br H Cl A831 N(2-methoxyethyl)(methyl) Br H Cl A832 N(3-methoxypropyl)(methyl) Br H Cl A833 H H Br Cl A834 CH₃ H Br Cl A835 C₂H₅ H Br Cl A836 n-C₃H₇ H Br Cl A837 n-C₄H₉ H Br Cl A838 n-C₅H₁₁ H Br Cl A839 n-C₆H₁₃ H Br Cl A840 CF₃ H Br Cl A841 CH₂CF₃ H Br Cl A842 OCH₃ H Br Cl A843 OCH₂—CH₃ H Br Cl A844 OCH₂—CH₂—CH₃ H Br Cl A845 OCH₂—CH₂—CH₂—CH₃ H Br Cl A846 OCF₃ H Br Cl A847 OCHF₂ H Br Cl A848 OCH₂—CF₃ H Br Cl A849 Phenyl H Br Cl A850 Phenoxy H Br Cl A851 Benzyl H Br Cl A852 Cl H Br Cl A853 Br H Br Cl A854 I H Br Cl A855 NH₂ H Br Cl A856 NH-Phenyl H Br Cl A857 CN H Br Cl A858 NH-Benzyl H Br Cl A859 4-cyanophenyl H Br Cl A860 1,4-oxazepan-4-yl H Br Cl A861 4-Morpholinyl H Br Cl A862 4-Methylpiperazin-1-yl H Br Cl A863 N(2-methoxyethyl)(methyl) H Br Cl A864 N(3-methoxypropyl)(methyl) H Br Cl A865 H CH₃ H Cl A866 CH₃ CH₃ H Cl A867 C₂H₅ CH₃ H Cl A868 n-C₃H₇ CH₃ H Cl A869 n-C₄H₉ CH₃ H Cl A870 n-C₅H₁₁ CH₃ H Cl A871 n-C₆H₁₃ CH₃ H Cl A872 CF₃ CH₃ H Cl A873 CH₂CF₃ CH₃ H Cl A874 OCH₃ CH₃ H Cl A875 OCH₂—CH₃ CH₃ H Cl A876 OCH₂—CH₂—CH₃ CH₃ H Cl A877 OCH₂—CH₂—CH₂—CH₃ CH₃ H Cl A878 OCF₃ CH₃ H Cl A879 OCHF₂ CH₃ H Cl A880 OCH₂—CF₃ CH₃ H Cl A881 Phenyl CH₃ H Cl A882 Phenoxy CH₃ H Cl A883 Benzyl CH₃ H Cl A884 Cl CH₃ H Cl A885 Br CH₃ H Cl A886 I CH₃ H Cl A887 NH₂ CH₃ H Cl A888 NH-Phenyl CH₃ H Cl A889 CN CH₃ H Cl A890 NH-Benzyl CH₃ H Cl A891 4-cyanophenyl CH₃ H Cl A892 1,4-oxazepan-4-yl CH₃ H Cl A893 4-Morpholinyl CH₃ H Cl A894 4-Methylpiperazin-1-yl CH₃ H Cl A895 N(2-methoxyethyl)(methyl) CH₃ H Cl A896 N(3-methoxypropyl)(methyl) CH₃ H Cl A897 H H CH₃ Cl A898 CH₃ H CH₃ Cl A899 C₂H₅ H CH₃ Cl A900 n-C₃H₇ H CH₃ Cl A901 n-C₄H₉ H CH₃ Cl A902 n-C₅H₁₁ H CH₃ Cl A903 n-C₆H₁₃ H CH₃ Cl A904 CF₃ H CH₃ Cl A905 CH₂CF₃ H CH₃ Cl A906 OCH₃ H CH₃ Cl A907 OCH₂—CH₃ H CH₃ Cl A908 OCH₂—CH₂—CH₃ H CH₃ Cl A909 OCH₂—CH₂—CH₂—CH₃ H CH₃ Cl A910 OCF₃ H CH₃ Cl A911 OCHF₂ H CH₃ Cl A912 OCH₂—CF₃ H CH₃ Cl A913 Phenyl H CH₃ Cl A914 Phenoxy H CH₃ Cl A915 Benzyl H CH₃ Cl A916 Cl H CH₃ Cl A917 Br H CH₃ Cl A918 I H CH₃ Cl A919 NH₂ H CH₃ Cl A920 NH-Phenyl H CH₃ Cl A921 CN H CH₃ Cl A922 NH-Benzyl H CH₃ Cl A923 4-cyanophenyl H CH₃ Cl A924 1,4-oxazepan-4-yl H CH₃ Cl A925 4-Morpholinyl H CH₃ Cl A926 4-Methylpiperazin-1-yl H CH₃ Cl A927 N(2-methoxyethyl)(methyl) H CH₃ Cl A928 N(3-methoxypropyl)(methyl) H CH₃ Cl A929 H CH₃ CH₃ Cl A930 CH₃ CH₃ CH₃ Cl A931 C₂H₅ CH₃ CH₃ Cl A932 n-C₃H₇ CH₃ CH₃ Cl A933 n-C₄H₉ CH₃ CH₃ Cl A934 n-C₅H₁₁ CH₃ CH₃ Cl A935 n-C₆H₁₃ CH₃ CH₃ Cl A936 CF₃ CH₃ CH₃ Cl A937 CH₂CF₃ CH₃ CH₃ Cl A938 OCH₃ CH₃ CH₃ Cl A939 OCH₂—CH₃ CH₃ CH₃ Cl A940 OCH₂—CH₂—CH₃ CH₃ CH₃ Cl A941 OCH₂—CH₂—CH₂—CH₃ CH₃ CH₃ Cl A942 OCF₃ CH₃ CH₃ Cl A943 OCHF₂ CH₃ CH₃ Cl A944 OCH₂—CF₃ CH₃ CH₃ Cl A945 Phenyl CH₃ CH₃ Cl A946 Phenoxy CH₃ CH₃ Cl A947 Benzyl CH₃ CH₃ Cl A948 Cl CH₃ CH₃ Cl A949 Br CH₃ CH₃ Cl A950 I CH₃ CH₃ Cl A951 NH₂ CH₃ CH₃ Cl A952 NH-Phenyl CH₃ CH₃ Cl A953 CN CH₃ CH₃ Cl A954 NH-Benzyl CH₃ CH₃ Cl A955 4-cyanophenyl CH₃ CH₃ Cl A956 1,4-oxazepan-4-yl CH₃ CH₃ Cl A957 4-Morpholinyl CH₃ CH₃ Cl A958 4-Methylpiperazin-1-yl CH₃ CH₃ Cl A959 N(2-methoxyethyl)(methyl) CH₃ CH₃ Cl A960 N(3-methoxypropyl)(methyl) CH₃ CH₃ Cl A961 H C₂H₅ C₂H₅ Cl A962 CH₃ C₂H₅ C₂H₅ Cl A963 C₂H₅ C₂H₅ C₂H₅ Cl A964 n-C₃H₇ C₂H₅ C₂H₅ Cl A965 n-C₄H₉ C₂H₅ C₂H₅ Cl A966 n-C₅H₁₁ C₂H₅ C₂H₅ Cl A967 n-C₆H₁₃ C₂H₅ C₂H₅ Cl A968 CF₃ C₂H₅ C₂H₅ Cl A969 CH₂CF₃ C₂H₅ C₂H₅ Cl A970 OCH₃ C₂H₅ C₂H₅ Cl A971 OCH₂—CH₃ C₂H₅ C₂H₅ Cl A972 OCH₂—CH₂—CH₃ C₂H₅ C₂H₅ Cl A973 OCH₂—CH₂—CH₂—CH₃ C₂H₅ C₂H₅ Cl A974 OCF₃ C₂H₅ C₂H₅ Cl A975 OCHF₂ C₂H₅ C₂H₅ Cl A976 OCH₂—CF₃ C₂H₅ C₂H₅ Cl A977 Phenyl C₂H₅ C₂H₅ Cl A978 Phenoxy C₂H₅ C₂H₅ Cl A979 Benzyl C₂H₅ C₂H₅ Cl A980 Cl C₂H₅ C₂H₅ Cl A981 Br C₂H₅ C₂H₅ Cl A982 I C₂H₅ C₂H₅ Cl A983 NH₂ C₂H₅ C₂H₅ Cl A984 NH-Phenyl C₂H₅ C₂H₅ Cl A985 CN C₂H₅ C₂H₅ Cl A986 NH-Benzyl C₂H₅ C₂H₅ Cl A987 4-cyanophenyl C₂H₅ C₂H₅ Cl A988 1,4-oxazepan-4-yl C₂H₅ C₂H₅ Cl A989 4-Morpholinyl C₂H₅ C₂H₅ Cl A990 4-Methylpiperazin-1-yl C₂H₅ C₂H₅ Cl A991 N(2-methoxyethyl)(methyl) C₂H₅ C₂H₅ Cl A992 N(3-methoxypropyl)(methyl) C₂H₅ C₂H₅ Cl A993 H CH₃O H Cl A994 CH₃ CH₃O H Cl A995 C₂H₅ CH₃O H Cl A996 n-C₃H₇ CH₃O H Cl A997 n-C₄H₉ CH₃O H Cl A998 n-C₅H₁₁ CH₃O H Cl A999 n-C₆H₁₃ CH₃O H Cl A1000 CF₃ CH₃O H Cl A1001 CH₂CF₃ CH₃O H Cl A1002 OCH₃ CH₃O H Cl A1003 OCH₂—CH₃ CH₃O H Cl A1004 OCH₂—CH₂—CH₃ CH₃O H Cl A1005 OCH₂—CH₂—CH₂—CH₃ CH₃O H Cl A1006 OCF₃ CH₃O H Cl A1007 OCHF₂ CH₃O H Cl A1008 OCH₂—CF₃ CH₃O H Cl A1009 Phenyl CH₃O H Cl A1010 Phenoxy CH₃O H Cl A1011 Benzyl CH₃O H Cl A1012 Cl CH₃O H Cl A1013 Br CH₃O H Cl A1014 I CH₃O H Cl A1015 NH₂ CH₃O H Cl A1016 NH-Phenyl CH₃O H Cl A1017 CN CH₃O H Cl A1018 NH-Benzyl CH₃O H Cl A1019 4-cyanophenyl CH₃O H Cl A1020 1,4-oxazepan-4-yl CH₃O H Cl A1021 4-Morpholinyl CH₃O H Cl A1022 4-Methylpiperazin-1-yl CH₃O H Cl A1023 N(2-methoxyethyl)(methyl) CH₃O H Cl A1024 N(3-methoxypropyl)(methyl) CH₃O H Cl A1025 H H CH₃O Cl A1026 CH₃ H CH₃O Cl A1027 C₂H₅ H CH₃O Cl A1028 n-C₃H₇ H CH₃O Cl A1029 n-C₄H₉ H CH₃O Cl A1030 n-C₅H₁₁ H CH₃O Cl A1031 n-C₆H₁₃ H CH₃O Cl A1032 CF₃ H CH₃O Cl A1033 CH₂CF₃ H CH₃O Cl A1034 OCH₃ H CH₃O Cl A1035 OCH₂—CH₃ H CH₃O Cl A1036 OCH₂—CH₂—CH₃ H CH₃O Cl A1037 OCH₂—CH₂—CH₂—CH₃ H CH₃O Cl A1038 OCF₃ H CH₃O Cl A1039 OCHF₂ H CH₃O Cl A1040 OCH₂—CF₃ H CH₃O Cl A1041 Phenyl H CH₃O Cl A1042 Phenoxy H CH₃O Cl A1043 Benzyl H CH₃O Cl A1044 Cl H CH₃O Cl A1045 Br H CH₃O Cl A1046 I H CH₃O Cl A1047 NH₂ H CH₃O Cl A1048 NH-Phenyl H CH₃O Cl A1049 CN H CH₃O Cl A1050 NH-Benzyl H CH₃O Cl A1051 4-cyanophenyl H CH₃O Cl A1052 1,4-oxazepan-4-yl H CH₃O Cl A1053 4-Morpholinyl H CH₃O Cl A1054 4-Methylpiperazin-1-yl H CH₃O Cl A1055 N(2-methoxyethyl)(methyl) H CH₃O Cl A1056 N(3-methoxypropyl)(methyl) H CH₃O Cl A1057 H Br Cl H A1058 H Cl CH₃O H A1059 H CH₃O Cl H A1060 Cl CH₃ Cl H

Most preferred are the following compounds, their N-oxides and pharmaceutical acceptable salts:

-   2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one -   5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)ethyl)isoindolin-1-one -   5-((4-phenoxypyridin-3-yl)methoxy)-2-propylisoindolin-1-one -   2-butyl-5-((2-chloro-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one -   2-butyl-5-((2-chloro-4-iodopyridin-3-yl)methoxy)isoindolin-1-one -   5-(4-Phenyl-pyridin-3-ylmethoxy)-2-propyl-2,3-dihydro-isoindol-1-one -   5-(4-Phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one -   1-[4-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-phenyl]-butan-1-one -   [3-(1-oxo-2-propyl-2,3-dihydro-1H-isoindol-5-yloxymethyl)-pyridin-4-yl]-carbamic     acid tert-butyl ester, trifluoroacetate -   2-Butyl-5-(2,6-dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one -   5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one,     trifluoroacetate -   5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-ethyl-2,3-dihydro-isoindol-1-one -   2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one -   2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one -   2-butyl-5-((4-phenylpyridin-3-yl)methylamino)isoindolin-1-one -   2-butyl-5-((4-phenoxypyridin-3-yl)methylamino)isoindolin-1-one -   2-butyl-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)methylamino)-isoindolin-1-one -   5-((4-aminopyridin-3-yl)methylamino)-2-butylisoindolin-1-one -   2-butyl-5-((4-(phenylamino)pyridin-3-yl)methylamino)isoindolin-1-one -   4-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)benzonitrile -   2-butyl-5-((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methylamino)-isoindolin-1-one -   2-butyl-5-[(quinolin-3-ylmethyl)amino]-2,3-dihydro-1H-isoindol-1-one     trifluoroacetate -   2-butyl-5-[(pyridin-3-ylmethyl)amino]-2,3-dihydro-1H-isoindol-1-one -   7-chloro-2-cyclopropyl-5-{[(2,6-dimethyl-4-phenylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-cyclopropyl-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-({[4-(morpholin-4-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-({[4-(4-methylpiperazin-1-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2,3-dihydro-1H-isoindol-1-one -   2-butyl-7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one -   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one -   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-propyl-2,3-dihydro-1H-isoindol-1-one -   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-ethyl-7-methyl-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-((5-phenylpyridin-3-yl)methylamino)isoindolin-1-one -   5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one -   N-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)pivalamide -   2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)-methyl)-4-phenylpyridine     1-oxide -   2-butyl-5-{[(2-chloro-4-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   5-{[(6-bromo-2-chloropyridin-3-yl)methyl]amino}-2-butyl-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-{[(2,4-dichloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-{[(6-chloro-2-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-{[(2-chloro-6-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-{[(2-chloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   5-{[(2-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl]amino}-2-(2-methoxyethyl)-7-methyl-2,3-dihydro-1H-isoindol-1-one -   2-butyl-5-{[(2,4-dichloro-6-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one -   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one -   5-[(4-methoxypyridin-3-yl)methoxy]-2-propyl-2,3-dihydro-1H-isoindol-1-one -   7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-(2,2,2-trifluoroethyl)-2,3-dihydro-isoindol-1-one -   2-butyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one -   7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-propyl-2,3-dihydro-isoindol-1-one -   2-ethyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one -   2-butyl-5-[(2-methyl-4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one -   2-butyl-5-[(4-[1,4]oxazepan-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one -   2-butyl-5-({4-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one -   2-butyl-5-({4-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one -   2-butyl-5-({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one -   2-butyl-5-(4-methoxy-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one     and -   2-butyl-5-(4-morpholin-4-yl-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one.

The compounds according to the invention can be obtained by different routes. Compounds of formula I are generally preparable by a nucleophilic substitution reaction as described in scheme 1. Furthermore, if Z is NH and R^(b) is hydrogen, compounds of formula I are also accessible by an imin formation with subsequent reductive hydrogenation as described in scheme 2.

In scheme 1 the variables R¹, R^(a), R^(b), Q, X², X³, Y¹, Y², Y³, Y⁴ and Z are defined as described above. LG represents a leaving group, which can be replaced by any nucleophilic group. Examples of leaving groups are halogen; such as bromine or iodine or haloalkyl- or arylsulfonates; such as mesylate, tosylate and triflate. According to scheme 1 the compound II is reacted with compound III to form compound IV (=I) under the condition of a nucleophilic substitution reaction, see e.g. J. March, Advanced Organic Chemistry, fourth edition, Wiley-Interscience, New York, 1992, page 293 ff. and the literature cited therein. As it is well known to a person skilled in the art the addition of a base (auxiliary base) can be beneficial. Examples of bases are NaOH, K₂CO₃, KOH or organic bases like tertiary amines, e.g. triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) or 1,5-diazabicyclo[4.3.0]non-5-en (DBN) [J. March, Advanced Organic Chemistry, fourth edition, Wiley-Interscience, New York, 1992, page 293 ff.].

Compounds of the formula I and IV, respectively, wherein Z is S(O) or S(O)₂, can be prepared from the compounds of the formula I and IV, respectively, wherein Z is S by standard oxidation methods, as described e.g. in WO 2006/058753.

In scheme 2 the variables R¹, R^(a), Q, X², X³, X⁴, Y¹, Y², Y³ and Y⁴ are defined as described above. According to scheme 2 compound V and VI react to form the imin VII. This imin is reduced to form the compound VIII. The reduction can be performed with any reducing agent, preferably with borohydrides, in particular with NaCNBH₄, sodium triacetoxyborohydride and NaBH₄. For suitable reaction conditions see J. March, Advanced Organic Chemistry, fourth edition, Wiley-Interscience, New York, 1992, page 898 ff. and the literature cited therein.

The N-oxides may be prepared from the compounds of formula I according to conventional oxidation methods, for example by treating said compounds with an organic peracid; such as metachloroperbenzoic acid or 3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(11), 1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents; such as hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7), 1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society 123(25), 5962-5973 (2001)]. The oxidation may lead to pure mono-N-oxides or to a mixture of different N-oxides, which can be separated by conventional methods; such as chromatography.

The reactions are usually performed in an organic solvent, including aprotic organic solvent, e.g. substituted amides, lactams and ureas; such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethyl urea, cyclic ethers; such as dioxane, tetrahydrofurane, halogenated hydrocarbons; such as dichloromethane, and mixtures thereof as well as mixtures thereof with C₁-C₆-alkanols and/or water.

The reactions described above will be usually performed at temperatures ranging from −10° C. to 100° C., depending on the reactivity of the used compounds.

The utility of the compounds in accordance with the present invention as modulators of metabotropic glutamate receptor activity, in particular mGlu2 activity, may be demonstrated by methodology known in the art. The compounds of the present invention can be tested e.g. by evaluating intracellular Ca²⁺ concentrations in cells permanently expressing human mGlu receptor, the rat glutamate transporter rGLAST and the Galpha16 subunit of the G-protein complex under standard conditions in a fluorometric imaging plate reader (FLIPR, Molecular Devices, Union City, Calif. 94587, USA) by measuring the response of the cells to a test compound in the absence of presence of glutamate. The FLIPR assay is a common functional assay to monitor native or recombinant Galphaq-coupled receptors, and native or recombinant receptors normally linked to other G-protein signalling cascades, which are coupled to calcium through co-expression of an alpha subunit of a promiscuous or chimeric G-protein. In the assay the increase of intracellular calcium is measured through a calcium-dependent fluorescent dye (e.g. Fluo-4 AM) in the FLIPR instrument.

For the purpose of the present study, a cell line permanently expressing a human mGlu receptor, such as the mGlu2 receptor, the rat glutamate transporter rGLAST and the GalphaG16 may be generated by transfection as described in the examples. For selection of a suitable cell clone and also the subsequent measurements, the selected clone the cells will be plated on suitable multiwell plates in a suitable medium (e.g. DMEM Glutamax (GIBCO # 21885-025)/10% dialyzed FCS). Cells may be selected by gentamycin treatment as described in the examples. Cells will then be loaded with a suitable Ca²⁺ sensitive fluorescence dye, e.g. with 2 μM Fluo-4 AM (Molecular Probes, F14201). Cells will then be washed with a suitable buffer (e.g. HEPES) and the thus treated plates will be measured in a fluorometric imaging plate reader (e.g. FLIPR, Molecular Devices, Union City, Calif. 94587, USA).

The compounds of the present invention were tested in the above-described FLIPR assay using the selected cell clone. Increased intracellular calcium levels were quantified following addition of test compound (agonism), as well as following addition of a submaximal concentration of glutamate (potentiation).

For the determination of the effect of the test compound by itself (agonism) or by increasing the response to a submaximal concentration (e.g. 1 μM) of glutamate (potentiation), the resulting signal is determined by subtraction of the background fluorescence from the maximal fluorescent peak height of the respective response. In the FLIPR instrument the compound is given to the cell and its fluorescence response quantified by the FLIPR instrument (agonism). The concentration at which the compound exerts half its maximal effect is named the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced by the test substance is normalized to the maximal effect exerted by 100 μM glutamate (set at 100%).

After addition of the test compound to the plate, a submaximal concentration of glutamate (e.g. 1 μM glutamate) will be added. A potentiator enhances the response of the receptor to glutamate. The response to glutamate in the presence of test compound is quantified. The concentration at which the test compound is able to exert half its maximal potentiation effect to glutamate is named the ‘EC₅₀’. The maximal response to the submaximal concentration of glutamate (e.g. 1 micromolar glutamate) in the presence of test compound is normalized to the maximal effect exerted by 100 micromolar glutamate (set at 100%). Least squares curve fitting with a four-parameter equation is then applied to the resulting dose-response curve to determine the resulting EC₅₀ values (Graph Pad Prism).

A control cell line, HEK293 cells expressing permanently rGLAST and Galpha16 was also plated to a multiwell plate for parallel testing to verify specificity of the test compound for mGlu2 receptor agonism or potentiation.

The compounds of the invention can be further characterized by measurement of their efficacy and potency to inhibit forskolin-induced cAMP levels in these cells on their own (agonism) or to potentiate the effect of glutamate (potentiation). Cyclic AMP levels were quantified using Alphascreen technology (PerkinElmer Life and Analytical Sciences, 710 Bridgeport Avenue, Shelton, Conn. USA) as described by the manufacturer for determining the effects of Galphai coupled receptors.

The concentration at which a compound exerts half its maximal effect is named the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced by the test substance is normalized to the maximal effect exerted by 100 μM glutamate (100%). Least squares curve fitting with a four-parameter equation is then applied to the resulting dose-response curve to determine the resulting EC₅₀ values (Graph Pad Prism).

In particular, the compounds of the following examples had activity in potentiating the mGlu2 receptor in the aforementioned assays, generally with an EC₅₀ of not more than about 10 μM. Preferred compounds within the present invention had activity in potentiating the mGlu2 receptor in the aforementioned assays with an EC₅₀ of less than 1 μM, in particular less than 0.5 μM, more preferably of at most 0.2 μM, of at most 0.1 μM. Such a result is indicative of the intrinsic activity of the compounds in use as positive modulators of mGlu2 receptor activity.

As stated above, the compounds of the present invention are positive modulators of metabotropic glutamate (mGluR) receptor function, in particular they are positive modulators of mGlu2 receptors. Thus, the compounds of the present invention can be used for treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including one or more of the following conditions or diseases: acute neurological and psychiatric disorders; such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, disorders associated with substance tolerance, disorders associated with substance withdrawal (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.

Of the disorders above, the treatment of schizophrenia, anxiety, depression, substance-related disorders, migraine, and epilepsy are of particular importance.

Therefore, the present invention relates to a method for treating a medical disorder, selected from neurological and psychiatric disorders associated with glutamate dysfunction, said method comprising administering an effective amount of at least one compound of the present invention to a subject in need thereof.

The compounds of the present invention frequently show an affinity towards the serotonin 5HT_(2A) receptor. In particular the compounds of the present invention are antagonist of the serotonin 5HT_(2A) receptor and have binding constants Ki(5HT_(2A)) below 1 μM, in particular of at most 0.5 μM, more preferably at most 250 nM or especially at most 100 nM. Thus the compounds of the present invention are particularly useful for treating the above mentioned disorders, in particular psychiatric disorders, such as schizophrenia, psychosis, cognitive disorders, drug abuse (i.e. disorders associated with substance tolerance, disorders associated with substance withdrawal (including substances; such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder). The affinity towards the 5HT2A receptor as well as the antagonistic action can be determined by routine screening techniques, a skilled person is familiar with (for reviews see e.g. D. E. Nichols, Hallocinogens, in Pharmacology & Therapeutics 101 (2004) 131-181, J. A. Lieberman et al. Biol. Psychiatry 44 (1998) 1099-1117, S. Miyamoto et al., Mol. Psychiatry. 10 (2005), 79-104).

The subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom potentiation of metabotropic glutamate receptor activity is desired. The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes; wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The terms “administration” of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

A preferred embodiment of the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a N-oxide and/or a pharmaceutically acceptable salt thereof. In another preferred embodiment the present invention provides a method for preventing or treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder.

In another preferred embodiment the present invention provides a method for treating substance-related disorders, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. In another preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. In yet another preferred embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof.

Of the neurological and psychiatric disorders associated with glutamate dysfunction which are treated according to the present invention, the treatment of schizophrenia, anxiety, depression, migraine, substance-related disorders, especially substance dependence, substance tolerance, substance withdrawal, and epilepsy are particularly preferred. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder.

Thus, in a preferred embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including schizophrenia and other psychotic disorders. These include: disorders having psychotic symptoms as the defining feature. The term psychotic refers to delusions, prominent hallucinations, disorganized speech, disorganized or catatonic behavior. The disorder includes: paranoid, disorganized, catatonic, undifferentiated, and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, and psychotic disorder not otherwise specified. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular schizophrenia, and that these systems evolve with medical scientific progress. Thus, the term “schizophrenia” is intended to include like disorders that are described in other diagnostic sources.

In another preferred embodiment, the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein the term “anxiety” includes treatment of those anxiety disorders and related disorder as described in the DSM-IV. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress. Thus, the term “anxiety” is intended to include like disorders that are described in other diagnostic sources.

In another preferred embodiment, the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a N-oxide and/or a pharmaceutically acceptable salt thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including depression and related disorders. Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder. As used herein the term “depression” includes treatment of those depression disorders and related disorder as described in the DSM-1V.

In another preferred embodiment, the present invention provides a method for treating substance-related disorders, especially substance dependence, substance abuse, substance tolerance, and substance withdrawal, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including disorders related to taking a drug of abuse (including alcohol), to the side effects of a medication, and to toxin exposure. Substances include alcohol, amphetamine and similarly acting sympathomimetics, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (PCP) or similarly acting arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also, polysubstance dependence and other unknown substance-related disorders are included. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular substance-related disorders, and that these systems evolve with medical scientific progress. Thus, the term “substance-related disorder” is intended to include like disorders that are described in other diagnostic sources.

In another preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. In one of the available sources of diagnostic tools, Dorland's Medical Dictionary (23'rd Ed., 1982, W. B. Saunders Company, Philadelphia, Pa.), migraine is defined as a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia. As used herein the term “migraine includes these periodic headaches, both temporal and unilateral, the associated irritability, nausea, vomiting, constipation or diarrhea, photophobia, and other associated symptoms. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress.

In another preferred embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I, a tautomer and/or a pharmaceutically acceptable salt thereof. At present, there are several types and subtypes of seizures associated with epilepsy, including idiopathic, symptomatic, and cryptogenic. These epileptic seizures can be focal (partial) or generalized. They can also be simple or complex. Epilepsy is described in the art, such as Epilepsy: A comprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley (Lippincott-Raven, Philadelphia, 1997). At present, the International Classification of Diseases, Ninth Revision, (ICD-9) provides a diagnostic tool including epilepsy and related disorders. These include: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with impairment of consciousness, partial epilepsy without impairment of consciousness, infantile spasms, epilepsy partialis continua, other forms of epilepsy, epilepsy, unspecified, NOS. As used herein the term “epilepsy” includes these all types and subtypes. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including epilepsy, and that these systems evolve with medical scientific progress.

In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require potentiation of metabotropic glutamate receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. When treating, preventing, controlling, ameliorating, or reducing the risk of neurological and psychiatric disorders associated with glutamate dysfunction or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams, hi the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The compounds according to the present invention are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents, including an mGluR agonist.

The term “potentiated amount” refers to an amount of an mGluR agonist, that is, the dosage of agonist which is effective in treating the neurological and psychiatric disorders described herein when administered in combination with an effective amount of a compound of the present invention. A potentiated amount is expected to be less than the amount that is required to provide the same effect when the mGluR agonist is administered without an effective amount of a compound of the present invention.

A potentiated amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining a potentiated amount, the dose of an mGluR agonist to be administered in combination with a compound of formula I, a number of factors are considered by the attending diagnostician, including, but not limited to: the mGluR agonist selected to be administered, including its potency and selectivity; the compound of formula Ito be coadministered; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the modes of administration; the bioavailability characteristics of the preparations administered; the dose regimens selected; the use of other concomitant medication; and other relevant circumstances.

A potentiated amount of an mGluR agonist to be administered in combination with an effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day and is expected to be less than the amount that is required to provided the same effect when administered without an effective amount of a compound of formula I. Preferred amounts of a co-administered mGlu agonist are able to be determined by one skilled in the art. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula I. When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I is preferred. However, the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by conventional routes of administration, including parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration.

The compounds of the present invention may be formulated alone or together with further active compounds, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically excipients. Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound. Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4^(th) edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to the invention are optionally mixed or diluted with one or more excipients.

The following examples are intended for further illustration of the present invention.

PREPARATION EXAMPLES

Abbreviations used in the Examples that follow are: DCC dicyclohexylcarbodiimide; DCM dichloromethane; DMA N,N-dimethylacetamide; DMAP 4-dimethylaminopyridine; DMF dimethylformamide; DMSO dimethylsulfoxide; Et₂O diethyl ether; EtOAc ethyl acetate; MeCN acetonitrile; MeOH methanol; RT room temperature; sat. saturated solutions; TFA trifluoroacetic acid; THF tetrahydrofuran; MP-CNBH₃ macroporous cyanoborohydride.

Preparative Example 1 ethyl 4-phenoxynicotinate

DCC (5.24 g, 25.4 mmol) was added in portions over 10 min to a solution of 4-chloronicotinic acid (2.00 g, 12.7 mmol), ethanol (1.75 g, 38.1 mmol) and DMAP (0.19 g, 1.52 mmol) in DMF (20 mL) at 0° C. After stiffing for 1 h the reaction mixture was allowed to warm to room temperature and stirred overnight. Water (100 mL) was added and the solid formed was filtered off. The filtrate was extracted with DCM, washed with water, dried (MgSO₄) and the solvent was removed in vacuo. The crude ethyl 4-chloronicotinate (5.8 g) was dissolved in DMF (15 mL). Phenol (2.86 g, 30.4 mmol), copper powder (0.48 g, 7.59 mmol), copper iodide (0.72 g, 3.80 mmol) and K₂CO₃ (4.20 g, 30.4 mmol) were added. The reaction mixture was heated to 80° C. for 3 h then allowed to cool to room temperature and left overnight without stirring. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with aqueous NaOH solution (1 M), water and dried over MgSO₄. Purification by flash chromatography (DCM/EtOAc, gradient 1-10% EtOAc) provided ethyl 4-phenoxynicotinate (1.59 g, 51% over 2 steps). ESI-MS [M+H]⁺=244.1.

Preparative Example 2 (4-(phenylamino)pyridin-3-yl)methanol

A mixture of 4-chloronicotinic acid (150 mg, 0.952 mmol) and aniline (177 mg, 1.90 mmol) in MeCN (2 mL) was stirred and heated in the microwave (80° C., 300 W) for 1 h. The solid material was filtered off and the solvent was removed in vacuo. The crude 4-(phenylamino)nicotinic acid (202 mg) obtained was dissolved in THF (25 mL). After dropwise addition of LiAlH₄ (1 M solution in THF, 3.77 mL, 3.77 mmol) at 0° C., the reaction mixture was stirred for 30 min, allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (0.4 mL) at 0° C. and excess EtOAc was added. All solid material was filtered off and the solvent was removed in vacuo. Trituration with Et₂O provided (4-(phenylamino)pyridin-3-yl)methanol (115 mg, 60% over 2 steps). ESI-MS [M+H]⁺=201.1.

Preparative Example 3 4-(benzylamino)nicotinic acid

A mixture of 4-chloronicotinic acid (300 mg, 1.90 mmol) and benzylamine (408 mg, 3.81 mmol) in MeCN (3 mL) was stirred and heated in the microwave (80° C., 200 W) for 1 h. The solution obtained was partitioned between water and EtOAc. The precipitate formed was filtered off, washed with water, EtOAc and dried in vacuo. 4-(benzylamino)nicotinic acid was obtained as a colourless solid (147 mg, 34%). ESI-MS [M+H]⁺=229.1.

Preparative Example 4 4-phenylnicotinaldehyde

4-bromonicotinaldehyde (150 mg, 0.81 mmol), phenylboronic acid (98 mg, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (46.6 mg, 0.05 mmol) were mixed in dioxane (3.5 mL). Na₂CO₃ (2 M solution in water, 0.81 mL, 1.63 mmol) was added and the reaction mixture was stirred and heated in the microwave (110° C., 150 W) for 30 min. After addition of excess water followed by extraction with EtOAc, the combined organic layers were filtered (celite) and dried (MgSO₄). Purification by flash chromatography (heptane/EtOAc, gradient 5-40% EtOAc) provided 4-phenylnicotinaldehyde (75 mg, 48%) as a dark yellow gum. ESI-MS [M+H]⁺=279.1.

The following intermediates were prepared in a manner analogous to the preparation of 4-phenylnicotinaldehyde:

Preparative Example 5 4-(4-(trifluoromethyl)phenyl)nicotinaldehyde

Prepared by analogy to preparative example 4.

ESI-MS [M+H]⁺=252.0.

Preparative Example 6 4-(3-formylpyridin-4-yl)benzonitrile

Prepared by analogy to preparative example 4.

ESI-MS [M+H]⁺=209.1.

Preparative Example 7 (2-chloro-4-phenylpyridin-3-yl)methanol

Starting from (2-chloro-4-iodopyridin-3-yl)methanol. ESI-MS [M+H]⁺=269.9

Preparative Example 8 (2,6-dimethyl-4-phenylpyridin-3-yl)methanol

LiAlH₄ (1 M solution in THF, 8.93 mL, 8.93 mmol) was added dropwise to a solution of ethyl 2,6-dimethyl-4-phenylnicotinate (940 mg, 3.57 mmol) in THF (38 mL) at 0° C. After stirring for 45 min, the reaction mixture was allowed to warm to room temperature and the stirring was continued for 75 min Water (0.2 mL) was added at 0° C. followed by NaOH (2 M, 0.2 mL) and water (0.2 mL). After the addition of excess EtOAc and filtration, the solvent was removed in vacuo providing (2,6-dimethyl-4-phenylpyridin-3-yl)methanol as a pale yellow gum (780 mg, >99%). ESI-MS [M+H]⁺=214.1.

The following intermediates were prepared in a manner analogous to the preparation of (2,6-dimethyl-4-phenylpyridin-3-yl)methanol:

Preparative Example 9 4-phenoxypyridin-3-yl)methanol

ESI-MS [M+H]+=202.1.

Preparative Example 10 4-(phenylamino)pyridin-3-yl)methanol

Starting from 4-(phenylamino)nicotinic acid using 4 eq of LiAlH₄ yielded the title compound. ESI-MS [M+H]⁺=201.1.

Preparative Example 11 (4-(benzylamino)pyridin-3-yl)methanol

Starting from 4-(benzylamino)nicotinic acid using 4 eq of LiAlH₄ yielded the title compound. ESI-MS [M+H]⁺=215.1.

Preparative Example 12 (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate

NEt₃ (0.60 mL, 4.31 mmol) and methanesulphonyl chloride (0.20 mL, 2.59 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methanol (460 mg, 2.16 mmol) in DCM (40 mL) at 0° C. After stirring for 40 min at 0° C. the reaction mixture was diluted with DCM, washed with sat. aqueous NaHCO₃ solution, water and dried (MgSO₄). Removal of the solvent provided crude (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate which was used without further purification (650 mg).

Preparative Example 13 4-phenoxynicotinaldehyde

MnO₂ (289 mg, 3.33 mmol) was added to a solution of (4-phenoxypyridin-3-yl)methanol (70 mg, 0.33 mmol) in THF (10 mL). After stiffing overnight the reaction mixture was filtered (celite). Removal of the solvent provided 4-phenoxynicotinaldehyde (70 mg, 95%). MS [M+H]⁺=200.1.

The following intermediates were prepared in a manner analogous to the preparation of 4-phenoxynicotinaldehyde:

Preparative Example 14 4-(phenylamino)nicotinaldehyde

ESI-MS [M+H]⁺=199.1.

Preparative Example 15 4-(benzylamino)nicotinaldehyde

ESI-MS [M+H]⁺=213.1.

Example 1 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one

2-Butyl-5-hydroxyisoindolin-1-one (366 mg, 1.78 mmol), K₂CO₃ (493 mg, 3.57 mmol) and KI (296 mg, 1.78 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate (520 mg, 1.78 mmol) in DMF (18 mL). After stirring overnight at room temperature (rt), water was added and the pH was adjusted to 13-14 using aqueous NaOH (1 M). The reaction mixture was extracted with EtOAc, the combined organic layers were washed with water, dried with MgSO₄ and the solvent was removed in vacuo. Purification by flash chromatography (DCM/MeOH, gradient 1-5% MeOH) provided 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one (140 mg, 19%). ESI-MS [M+H]⁺=401.2.

The following compounds of example 2-5 were prepared in a manner analogous to the preparation of 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one:

Example 2 5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)ethyl)isoindolin-1-one

ESI-MS [M+H]⁺=457.2.

Example 3 5-((4-phenoxypyridin-3-yl)methoxy)-2-propylisoindolin-1-one

ESI-MS [M+H]⁺=375.2.

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.95 (s, 1H); 8.70 (d, 1H); 7.60 (m, 3H), 7.40 (t, 1H); 7.35 (s, 1H); 7.30 (d, 2H); 7.20 (d, 1H); 7.05 (d, 1H); 5.45 (s, 2H); 4.40 (s, 2H); 3.45 (t, 2H); 1.60 (m, 2H); 0.85 (t, 3H).

Example 4 2-butyl-5-((2-chloro-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one

ESI-MS [M+H]⁺=407.1.

Example 5 2-butyl-5-((2-chloro-4-iodopyridin-3-yl)methoxy)isoindolin-1-one

ESI-MS [M+H]⁺=457.0.

Example 6 5-(4-Phenyl-pyridin-3-ylmethoxy)-2-propyl-2,3-dihydro-isoindol-1-one

ESI-MS [M+H]⁺=359.20

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (s, 1H); 8.65 (d, 1H); 7.55 (d, 1H); 7.45 (m, 6H); 7.10 (s, 1H); 7.00 (d, 1H); 5.10 (s, 2H); 4.35 (s, 2H); 3.45 (t, 2H); 1.60 (m, 2H); 0.85 (t, 3H).

Example 7 5-(4-Phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one

ESI-MS [M+H]⁺=429.10

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (s, 1H); 8.65 (d, 1H); 7.60 (d, 1H); 7.45 (m, 5H); 7.40 (d, 1H); 7.20 (s, 1H), 7.05 (d, 1H); 5.10 (s, 2H); 4.45 (s, 2H); 4.30 (m, 2H); 3.80 (m, 2H).

Example 8 [3-(1-oxo-2-propyl-2,3-dihydro-1H-isoindol-5-yloxymethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester, trifluoroacetate

ESI-MS [M+H]⁺=398.20

Example 9 2-Butyl-5-(2,6-dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one

ESI-MS [M+H]⁺=401.20

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.55 (d, 1H); 7.40 (m, 5H); 7.15 (s, 1H), 7.10 (s, 1H); 7.05 (d, 1H); 4.95 (s, 2H); 4.40 (s, 2 H); 3.45 (t, 2H); 2.60 (s, 3H); 2.50 (s, 3H); 1.55 (m, 2H); 1.30 (m, 2H); 0.85 (t, 3H).

Example 10 5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxyethyl)-2,3-dihydro-isoindol-1-one, trifluoroacetate

ESI-MS [M+H]⁺=457.20

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.75 (s, 1H); 7.60 (d, 1H); 7.50 (m, 5H); 7.20 (s, 1H), 7.05 (d, 1H); 5.10 (s, 2H); 4.45 (s, 2H); 4.30 (t, 2H); 3.80 (t, 2H); 2.80 (s, 3H); 2.70 (s, 3H).

Example 11 5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-ethyl-2,3-dihydroisoindol-1-one

ESI-MS [M+H]⁺=373.20

¹H-NMR (400 MHz, d₆-DMSO): δ [ppm] 7.55 (d, 1H); 7.45 (m, 5H); 7.15 (s, 1H), 7.10 (s, 1H); 7.05 (d, 1H); 4.95 (s, 2H); 4.40 (s, 2 H); 3.50 (q, 2H); 2.55 (s, 3H); 2.50 (s, 3H); 1.15 (t, 3H).

Example 12 5-[(4-methoxypyridin-3-yl)methoxy]-2-propyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS [M+H]⁺=313.10

Example 13 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one

5-Amino-2-butylisoindolin-1-one (63.1 mg, 0.309 mmol), K₂CO₃ (85 mg, 0.618 mmol) and KI (51.3 mg, 0.309 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate (90 mg, 0.309 mmol) in DMF (6 mL). After stirring overnight, water was added, the mixture was extracted with EtOAc, the combined organic layers were washed with water and dried (MgSO₄). Purification by flash chromatography (DCM/MeOH, gradient 2-8% MeOH) provided 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one (51 mg, 40%).

ESI-MS [M+H]⁺=400.2.

Example 14 2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one

5-amino-2-butylisoindolin-1-one (35.0 mg, 0.17 mmol), ZnCl₂ (14.0 mg, 0.10 mmol) and NaCNBH₄ (12.9 mg, 0.21 mmol) were consecutively added to a solution of 4-(trifluoromethyl)nicotinaldehyde (30.0 mg, 0.17 mmol) in MeOH (4 mL). After stirring overnight at room temperature excess water was added. The reaction mixture was extracted with EtOAc, the combined org. layers were washed with water, dried (MgSO₄) and the solvent was removed in vacuo. Purification by HPLC provided 2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one TFA (16.0 mg, 19%). ESI-MS [M+H]⁺=364.2.

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (m, 2H); 7.75 (d, 1H); 7.35 (d, 1H), 6.65 (m, 2H); 4.55 (s, 2H); 4.25 (s, 2H); 3.40 (t, 2H); 1.50 (m, 2H); 1.25 (m, 2H); 0.90 (t, 3H).

The following compounds were prepared in a manner analogous to the preparation of 2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one:

Example 15 2-butyl-5-((4-phenylpyridin-3-yl)methylamino)isoindolin-1-one

ESI-MS [M+H]⁺=372.2.

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (m, 2H); 7.70 (d, 1H); 7.60 (m, 5H), 7.30 (d, 1H); 6.55 (d, 1H); 6.50 (s, 1H); 4.35 (s, 2H); 4.25 (s, 2H); 3.40 (t, 2H); 1.50 (m, 2H); 1.25 (m, 2H); 0.90 (t, 3H).

Example 16 2-butyl-5-((4-phenoxypyridin-3-yl)methylamino)isoindolin-1-one

ESI-MS [M+H]⁺=388.2.

Example 17 2-butyl-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)methylamino)-isoindolin-1-one

ESI-MS [M+H]⁺=398.1.

Example 18 5-((4-aminopyridin-3-yl)methylamino)-2-butylisoindolin-1-one

Using 3 eq NaCNBH₄ and 0.9 eq ZnCl₂ for 8 days. ESI-MS [M+H]⁺=311.2.

Example 19 2-butyl-5-((4-(phenylamino)pyridin-3-yl)methylamino)isoindolin-1-one

Using 4.2 eq NaCNBH₄ and 1.2 eq ZnCl₂ for 8 days. ESI-MS [M+H]⁺=387.2.

Example 20 4-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)benzonitrile

ESI-MS [M+H+]=397.1.

Example 21 2-butyl-5-((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methylamino)-isoindolin-1-one

ESI-MS [M+H]⁺=440.2.

Example 22 2-butyl-5-[(pyridin-3-ylmethyl)amino]-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [2M+Na]⁺=613.30, [M+H⁺]=296.10

Example 23 7-chloro-2-cyclopropyl-5-{[(2,6-dimethyl-4-phenylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=418.20

Example 24 7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-cyclopropyl-2,3-dihydro-1H-isoindol-1-one

¹H NMR (500 MHz, DMSO): δ [ppm] 8.73 (d, J=4.9 Hz, 1H), 7.90 (d, J=5.2 Hz, 1 H), 6.77 (m, 1 H), 6.69 (d, J=4.9 Hz, 2 H), 4.39 (d, J=3.4 Hz, 2 H), 4.24 (s, 2 H), 2.82 (m, 1H), 0.68-0.83 (m, 4 H).

Example 25 2-butyl-5-({[4-(morpholin-4-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one

¹H NMR (500 MHz, DMSO) δ[ppm] 8.39 (s, 1H), 8.31 (d, J=5.5, 1H), 7.32 (d, J=8.3, 1H), 6.99 (d, J=5.5, 1H), 6.92 (t, J=5.8, 1H), 6.64 (d, J=8.3, 2H), 4.32-4.22 (m, 4H), 3.81-3.73 (m, 4H), 3.38 (t, 2H), 3.05-2.97 (m, 4H), 1.56-1.46 (m, 2H), 1.25 (dt, J=7.3, 14.6, 2H), 0.88 (t, J=7.4, 3H).

Example 26 2-butyl-5-({[4-(4-methylpiperazin-1-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one

¹H NMR (500 MHz, DMSO) δ[ppm] 8.38 (s, 1 H), 8.28 (d, J=5.5 Hz, 1 H), 7.33 (d, J=8.8 Hz, 1 H), 6.97 (d, J=5.5 Hz, 1 H), 6.92 (t, J=5.8 Hz, 1 H), 6.61-6.67 (m, 2 H), 4.23-4.31 (m, 3 H), 3.33-3.41 (m, 3 H), 3.02 (t, J=4.4 Hz, 3 H), 2.47-2.56 (m, 5 H), 2.21-2.27 (m, 3 H), 1.48-1.55 (m, 2 H), 1.21-1.29 (m, 2 H), 0.89 (t, J=7.3 Hz, 3 H)

Example 27 2-butyl-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=412.10;

¹H NMR (chloroform-d, 500 MHz): δ[ppm]=8.57 (d, J=4.9 Hz, 1 H), 7.57 (d, J=5.2 Hz, 1 H), 6.52 (d, 2H), 4.58 (s, 2 H), 4.25 (s, 2 H), 3.54 (t, J=7.3 Hz, 2 H), 3.12 (s br, 1 H), 2.64 (s, 3 H), 1.61 (t, J=7.3 Hz, 2 H), 1.35-1.40 (m, 2 H), 0.95 (t, J=7.3 Hz, 3 H).

Example 28 2-butyl-7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: 434.10, [M]⁺=432.10;

¹H NMR (DMSO-d₆, 500 MHz): δ[ppm]=8.73 (d, J=5.2 Hz, 1H), 7.90 (d, J=4.9 Hz, 1 H), 6.74-6.78 (m, 2 H), 6.69-6.71 (m, 1 H), 4.41 (br. s., 2 H), 4.31 (s, 2 H), 3.42 (t, J=7.0 Hz, 2 H), 1.54 (quin, J=7.3 Hz, 2 H), 1.25-1.31 (m, 2 H), 0.91 ppm (t, J=7.3 Hz, 3 H)

Example 29 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H⁺]=438.10;

Example 30 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-propyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=398.10;

¹H NMR (DMSO-d₆, 500 MHz): δ [ppm]=8.71 (d, J=5.2 Hz, 1H), 7.87 (d, J=5.2 Hz, 1 H), 6.59 (s, 1 H), 6.47 (s, 1 H), 4.38 (s, 2 H), 4.26 (s, 2 H), 3.37 (t, J=7.2 Hz, 2 H), 2.50 (s, 3 H), 1.54-1.59 (m, 2 H), 0.86 ppm (t, J=7.5 Hz, 3 H)

Example 31 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-ethyl-7-methyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=384.05;

¹H NMR (DMSO-d6, 500 MHz): δ [ppm]=8.71 (d, J=4.9 Hz, 1H), 7.88 (d, J=4.9 Hz, 1 H), 6.59 (s, 1 H), 6.47 (s, 1 H), 6.38 (br. s., 1 H), 4.38 (br. s., 2 H), 4.27 (s, 2 H), 3.41-3.47 (m, 2 H), 2.49 (br. s., 3 H), 1.13 ppm (t, J=7.3 Hz, 3 H)

Example 32 2-butyl-5-((5-phenylpyridin-3-yl)methylamino)isoindolin-1-one

ESI-MS: [M+H]⁺=372.2.

Example 33 2-butyl-5-{[(2-chloro-4-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=344.10

Example 34 5-{[(6-bromo-2-chloropyridin-3-yl)methyl]amino}-2-butyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=408.00

Example 35 2-butyl-5-{[(2,4-dichloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=364.05

Example 36 2-butyl-5-{[(6-chloro-2-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=360.10

Example 37 2-butyl-5-{[(2-chloro-6-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=360.10

Example 38 2-butyl-5-{[(2-chloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=330.10

Example 39 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino-2-(2-methoxyethyl)-7-methyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=414.10

Example 40 2-butyl-5-{[(2,4-dichloro-6-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

¹H NMR (DMSO-d₆, 500 MHz): δ[ppm]=7.63 (d, 1H), 7.18 (s, 1H), 6.75 (m, 2H), 4.61 (s, 2H), 4.27 (s, 2H), 3.56 (r, 2H), 2.51 (s, 3H), 1.61 (quint, 2H), 1.36 (quint, 2H), 0.94 (t, J=7.3 Hz, 3H).

Example 41 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=400.10

Example 42 5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one

5-Amino-2-butylisoindolin-1-one (48.1 mg, 0.236 mmol) was added to a solution of 4-(benzylamino)nicotinaldehyde (50 mg, 0.236 mmol) in acetic acid (0.5 mL). Sodium triacetoxyborohydride (100 mg, 0.471 mmol) was added and the reaction mixture was stirred for 2 days. After the addition of more triacetoxyborohydride (50 mg, 0.235 mmol) and stirring for 6 h, water and sat aqueous NaHCO₃ solution were added. The mixture was extracted with EtOAc, the combined org. layers washed with water and dried (MgSO₄). Purification by HPLC provided 5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one (16 mg, 13%). ESI-MS [M+H+]=401.2.

Example 43 N-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)pivalamide

5-Amino-2-butylisoindolin-1-one (49.5 mg, 0.242 mmol) was added to a solution of N-(3-formylpyridin-4-yl)pivalamide (50 mg, 0.242 mmol) in acetic acid (1 mL). After stiffing for 5 days, water and sat aqueous NaHCO₃ solution were added. The mixture was extracted with EtOAc, the combined organic layers were washed with water, dried over MgSO₄ and the solvent was removed in vacuo. The residue obtained was dissolved in MeOH (3 mL) and NaBH₄ (18.3 mg, 0.485 mmol) was added. After stirring overnight, water and sat. aqueous NaHCO₃ solution were added. Extraction with EtOAc, washing of the combined organic layers with water and drying over MgSO₄ provided the crude product which was purified by HPLC (24 mg, 19%). ESI-MS [M+H]⁺=395.2.

Example 44 2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)-methyl)-4-phenylpyridine 1-oxide

3-Chloroperbenzoic acid (19.3 mg, 0.112 mmol) was added to a solution of 5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)-ethyl)isoindolin-1-one (40 mg, 0.074 mmol, 85% pure) in DCM. After stiffing overnight the reaction mixture was diluted with DCM, sat. aqueous NaHCO₃ solution was added. Extraction with DCM, washing of the combined organic layers with water, drying over MgSO₄ followed by purification by HPLC provided 2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)methyl)-4-phenylpyridine 1-oxide (23 mg, 64%). ESI-MS [M+H]+=473.1.

The following compounds were prepared in an analogous manner.

Example 45 7-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-1-one Example 46 2-Butyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=395.20

Example 47 7-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-propyl-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid Example 48 2-Ethyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=367.20

Example 49 2-Butyl-5-[(2-methyl-4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=395.20

Example 50 2-Butyl-5-[(4-[1,4]oxazepan-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=395.20

Example 51 2-Butyl-5-({4-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=397.20

Example 52 2-Butyl-5-({4-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=397.20

Example 53 2-Butyl-5-({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one; Compound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=383.20

Example 54 2-Butyl-5-(4-methoxy-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one

ESI-MS: [M+H]⁺=327.10

Example 55 2-Butyl-5-(4-morpholin-4-yl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one

ESI-MS: [M+H]⁺=382.20; [2M+Na]=675.30

Biological Tests:

I Generation of a HEK293 Cell Clones Permanently Expressing mGlu Receptors and Functional Evaluation of the Cells

a) mGlu2 Receptor

For the purpose of the present study, a cell line permanently expressing the human mGlu2 receptor, the rat glutamate transporter rGLAST and the alpha subunit of G16 was generated by transfection. Briefly, HEK293 cells were seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶ cells in DMEM with glutamax (Invitrogen, GIBCO # 21885-025), 10% dialyzed Fetal Calf Serum (Invitrogen, Gibco # 26400-044), and incubated at 37° C. over night. The following day cells were transfected with Lipofectamine (Invitrogen, Gibco #18324-012) as recommended by the manufacturer, using linearized pcDNA3.1 (V5/His)-hmGlu2 receptor (ScaI) and pcDNA3.1 Zeo-Ga16 IRES rGLAST (SspI). After transfection the cells were selected in DMEM Glutamax Medium (Invitrogen, GIBCO # 21885-025), containing 10% dialyzed fetal calf serum (FCS; (Invitrogen, Gibco # 26400-044), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 250 μg/ml Zeozin. Single clones were isolated manually and further subcloned by serial dilution.

The function of the mGlu2 receptor was determined by evaluating intracellular Ca²⁺ concentrations under standard conditions in a fluorometric imaging plate reader (FLIPR, Molecular Devices, Union City, Calif. 94587, USA) by measuring the response of the cells to a test compound. The FLIPR assay is a common functional assay to monitor native or recombinant Galphaq-coupled receptors, and native or recombinant receptors normally linked to other G-protein signalling cascades, which are coupled to calcium through co-expression of an alpha subunit of a promiscuous or chimeric G-protein. In the assay the increase of intracellular calcium is measured through a calcium-dependent fluorescent dye (e.g. Fluo-4 AM) in the FLIPR instrument.

For selection of a suitable cell clone and also the subsequent measurements of the selected clone, 4×10⁴ cells/well were plated on poly-D-lysine coated Biocoat-plates multiwell 96 in DMEM Glutamax (GIBCO # 21885-025)/10% dialyzed FCS over night. The following day, the medium was aspirated and exchanged for glutamate-free DMEM (Gibco # 21969-035), without FCS or glutamine, containing 50 μg/ml gentamycin (Gibco # 15750). Cells were again incubated over night. Before the measurement, cells were loaded with 2 μM Fluo-4 AM (Molecular Probes, F14201; stock solution 1 mM in DMSO) and 0.02% Pluronic F127 (Molecular Probes, P3000; stock solution 10% in DMSO) in DMEM medium (Gibco # 21969-035) for 45 minutes at 37° C. in a final volume of 100 μl per well. Finally, the plates were washed in a BioTec cell washer with HBSS, containing 20 mM HEPES. The end-volume in each well was 100 μl. The plates were subsequently measured in a fluorometric imaging plate reader (FLIPR, Molecular Devices, Union City, Calif. 94587, USA).

The compounds of the present invention were tested in the above-described FLIPR assay using the selected cell clone. Increased intracellular calcium levels were quantified following addition of test compound (agonism), as well as following addition of a submaximal concentration of 1 micromolar (1 μM) glutamate (potentiation).

For the determination of the effect of the test compound by itself (agonism) or by increasing the response to a submaximal concentration (e.g. 1 μM) of glutamate (potentiation), the resulting signal is determined by subtraction of the background fluorescence from the maximal fluorescent peak height of the respective response. In the FLIPR instrument the compound is given to the cell and its fluorescence response quantified by the FLIPR instrument (agonism). The concentration at which the compound exerts half its maximal effect is named the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced by the test substance is normalized to the maximal effect exerted by 100 μM glutamate (set at 100%).

Ten minutes after addition of the test compound to the plate, 1 μM glutamate is added. A potentiator enhances the response of the receptor to glutamate. The response to glutamate in the presence of test compound is quantified. The concentration at which the test compound is able to exert half its maximal potentiation effect to glutamate is named the ‘EC₅₀’. The maximal response to 1 micromolar glutamate in the presence of test compound is normalized to the maximal effect exerted by 100 μM glutamate (set at 100%). Least squares curve fitting with a four-parameter equation is then applied to the resulting dose-response curve to determine the resulting EC₅₀ values (Graph Pad Prism). A control cell line, HEK293 cells expressing permanently rGLAST and Galpha16 was also plated at 4×10⁴ cells/well for parallel testing to verify specificity of the test compound for mGlu2 receptor agonism or potentiation. The EC₅₀ values are given in table I.

Highly potent or key compounds were further characterized by measurement of their efficacy and potency to inhibit forskolin-induced cAMP levels in these cells on their own (agonism) or to potentiate the effect of glutamate (potentiation). Cyclic AMP levels were quantified using Alphascreen technology (PerkinElmer Life and Analytical Sciences, 710 Bridgeport Avenue, Shelton, Conn. USA) as described by the manufacturer for determining the effects of Galphai coupled receptors. The concentration at which a compound exerts half its maximal effect is named the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced by the test substance is normalized to the maximal effect exerted by 100 μM glutamate (100%). Least squares curve fitting with a four-parameter equation is then applied to the resulting dose-response curve to determine the resulting EC₅₀ values (Graph Pad Prism).

The compounds of the following examples had activity in potentiating the mGlu2 receptor in the aforementioned assays, generally with an EC₅₀ of not more than about 10 μM. Preferred compounds within the present invention had activity in potentiating the mGlu2 receptor in the aforementioned assays with an EC₅₀ of less than about 1 μM. Such a result is indicative of the intrinsic activity of the compounds in use as potentiators of mGlu2 receptor activity.

TABLE I EXAMPLE EC₅₀ ¹⁾ 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 +++ 7 +++ 8 + 11 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 19 ++ 20 +++ 21 +++ 22 + 23 +++ 24 +++ 25 ++ 26 + 33 ++ 34 ++ 35 +++ 36 ++ 37 ++ 38 + 39 ++ 42 + 43 ++ 44 +++ ¹⁾+++: EC₅₀ < 0.5 μM ++: 0.5 μM ≦ EC₅₀ ≦ 2 μM +: 2 μM < EC₅₀ < 10 μM

b) mGlu3 Receptor

For the purpose of the present study, we generated by transfection a cell line permanently expressing the human mGlu3 receptor, the rat glutamate transporter rGLAST and the alpha subunit of G16. Briefly, HEK293 cells were seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶ cells in DMEM with glutamax (Invitrogen, GIBCO # 21885-025), 10% dialyzed Fetal Calf Serum (Invitrogen, Gibco # 26400-044), and incubated at 37° C. over night. The following day cells were transfected with Lipofectamine (Invitrogen, Gibco #18324-012) as recommended by the manufacturer, using linearized pcDNA3.1 (V5/His)-hmGlu3 receptor (ScaI) and pcDNA3.1 Zeo-Ga16 IRES rGLAST (SspI). After transfection the cells were selected in DMEM Glutamax Medium (Invitrogen, GIBCO # 21885-025), containing 10% dialyzed fetal calf serum (FCS; (Invitrogen, Gibco # 26400-044), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 250 μg/ml Zeozin. Single clones were isolated manually and further subcloned by serial dilution. Function was tested with FLIPR as described above.

c) mGlu4 Receptor

For the purpose of the present study, we generated by transfection a cell line permanently expressing human mGlu4 receptor, the rat glutamate transporter rGLAST and the alpha subunit of G15. Briefly, HEK293 cells were seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶ cells in DMEM glutamax, 10% dialyzed FCS, and incubated at 37° C. over night. The following day cells were transfected with Lipofectamine (Invitrogen, Karlsruhe, Germany) as recommended by the manufacturer, using linearised pcDNA3-hmGlu4 (SspI) and pcDNA3.1(+) Hygro-rGLAST IRES Gal5 (SspI). After transfection the cells were cultured in DMEM Glutamax Medium (Invitrogen), containing 10% dialyzed fetal calf serum (FCS; Invitrogen), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 150 μg/ml Hygromycin, and single clones were isolated manually and subcloned by serial dilution. Function was tested with FLIPR as described above.

d) mGlu7 Receptor

For the purpose of the present study, we generated by transfection a cell line permanently expressing human mGlu7a receptor, the rat glutamate transporter rGLAST and the alpha subunit of G15. Briefly, HEK293 cells were seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶ cells in DMEM glutamax, 10% dialyzed FCS, and incubated at 37° C. over night. The following day cells were transfected with Lipofectamine (Invitrogen, Karlsruhe, Germany) as recommended by the manufacturer, using linearised pcDNA3(−)-hmGlu7a (SspI). After transfection cells were cultured in DMEM Glutamax Medium (Invitrogen), containing 10% dialyzed fetal calf serum (FCS; Invitrogen), antibiotic/antimycotic (Invitrogen) and 800 μg/ml Geneticin (G418). Single clones were isolated manually, tested for reduction of cellular cAMP (alpha screen) and subcloned by FACS. Single cell clones were retested for cAMP reduction, and transfected with pcDNA3.1 (+) Hygro rGLAST IRES Gal5 (SspI). The transfection was done identical as described above. Cells were selected in DMEM Glutamax, 10% dialyzed FCS, antibiotic/antimycotic, 800 μg/ml G418 and 150 μg/ml Hygromycin. Single clones were isolated by serial dilution and tested by FLIPR as described above.

e) mGlu1 and 5 Receptors

For the purpose of the present study, we generated by transfection a cell line permanently expressing human mGlu5a and the rat glutamate transporter rGLAST. Briefly, cells were transfected with Lipofectamine (Invitrogen, Karlsruhe, Germany), using linearised pcDNA3-hmGlu5a (ScaI) and pIRES-rGlast (SspI). After transfection the cells were cultured in DMEM Glutamax Medium (Invitrogen), containing 10% dialyzed fetal calf serum (FCS; Invitrogen), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 150 μg/ml Hygromycin, and single clones were isolated manually. Identically, a cell line expressing mGlu1a was generated. Functional clones were selected using intracellular Ca²⁺ measurements with a fluorescence imaging plate reader (FLIPR) under standard conditions as described above. 

We claim:
 1. A compound of formula I

wherein X² is C—R²; X³ is C—R³; X⁴ is C—R⁴; Y¹ is N, C or C—R⁵; Y² is N, C or C—R⁶; Y³ is N, C or C—R⁷; Y⁴ is N, C or C—R⁸; provided that only the moiety Y¹, Y², Y³ or Y⁴ to which Z is bound to C and further provided at most one of Y¹, Y², Y³ or Y⁴ is N; Z is O, S, S(O), S(O)₂ or NR^(z); R^(z) is hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, or C₁-C₄-alkyl, which is unsubstituted or carries one radical selected from the group consisting of C₁-C₄-alkoxy and NR^(Z1)R^(Z2); where R^(Z1) and R^(Z2) are independently of each other selected from the group consisting of hydrogen, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, or R^(Z1) and R^(Z2) together with the nitrogen to which they are attached form a 5- or 6-membered N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from the group consisting of O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals; or R^(Z) is a radical SO₂R^(Z3) or a radical S(O)₂NR^(Z4)R^(Z5); where R^(Z3) is C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, phenyl or benzyl, wherein the phenyl ring in the last two mentioned radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals selected from the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, R^(Z4) and R^(Z5) have one of the meanings given for R^(Z1) and R^(Z2); Q is CH₂ or CH₂CH₂, where one or two of the hydrogen atoms in CH₂ or CH₂CH₂ may be replaced by halogen, C₁-C₄-alkyl or C₁-C₄-haloalkyl; R¹ is halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkoxy, C₃-C₃-cycloalkyl, a radical NR^(1a)R^(1b), C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, aryl, aryl-CH₂, aryloxy, hetaryl, hetaryloxy or hetaryl-CH₂, wherein the heterocyclyl, aryl and hetaryl ring in the last seven radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R^(1c); R^(1a) is hydrogen, C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, benzyl, phenyl or 5- or 6-membered hetaryl, wherein the phenyl and hetaryl rings in the last three radicals itself are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R^(1c); R^(1b) is hydrogen or C₁-C₄-alkyl; or NR^(1a)R^(1b) is a 3- to 10-membered mono- or bicyclic N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from the group consisting of O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 radicals R^(1c); R^(1c) is selected from the group consisting of halogen, CN, OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; R² is hydrogen; R³ and R⁴ are, independently of each other, selected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, phenyl, C₁-C₄-haloalkoxy, a radical (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(6c), where R^(6c) has one of the meanings given for R^(1c); R⁵ is hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkoxy, (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(6c), where R^(6c) has one of the meanings given for R^(1c); R⁶, R⁷, Ware, independently of each other, selected from the group consisting of hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(6c), where R^(6c) has one of the meanings given for R^(1c); R^(a) is C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkyl, which is unsubstituted or carries one radical selected from the group consisting of C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and a radical NR^(a1R) ^(a2), where R^(a1)and R^(a2) are independently of each other selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, a radical NR^(a3)R^(a4) or a radical N═C(R^(a5)R) ^(a6), where R^(a3) and R^(a5) are independently of each other selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl; R^(a4) and R^(a6) are independently of each other selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 10-membered, saturated heterocyclyl, 3- to 10-membered, saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the heterocycicyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R^(ac), where R^(ac) has one of the meanings given for R^(1c); R^(b) is hydrogen, halogen or C₁-C₄-alkyl; or a pharmaceutically acceptable salt or N-oxide thereof.
 2. The compound of claim 1, wherein R¹ is phenyl or phenoxy, wherein the phenyl ring in these radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(1c).
 3. The compound of claim 1, wherein R¹ is linear C₁-C₆-alkyl, branched C₃-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkoxy, halogen, C₃-C₆-cycloalkyl or C₁-C₆-haloalkyl.
 4. The compound of claim 1, wherein R¹ is a radical NR^(1a)R^(1b) or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R^(1c).
 5. The compound of claim 1, wherein Z is O or NH.
 6. The compound of claim 1, wherein X³ is C—R³, wherein R³ is hydrogen, chlorine, methyl or methoxy.
 7. The compound of claim 1, wherein X⁴ is C—R⁴, wherein R⁴ is hydrogen, chlorine, methyl or methoxy.
 8. The compound of claim 6, wherein X² is C—H, X³ is C—R³ and X⁴ is C—R⁴, wherein R³ and R⁴ are, independently selected from the group consisting of hydrogen, chlorine, methyl and methoxy.
 9. The compound of claim 1, wherein Y¹ is C—R⁵, Y² is C, Y³ is C—R⁷ and Y⁴ is N or C—R⁸.
 10. The compound of claim 1, wherein Y¹ is C—R⁵, Y³ is C, Y² is C—R⁶ and Y⁴ is N or C—R⁸.
 11. The compound of claim 1, wherein R⁵ is hydrogen, chlorine, methyl or methoxy.
 12. The compound of claim 1, wherein R⁶, R⁷ and R⁸, where present, are hydrogen.
 13. The compound of claim 1, wherein R^(a) is C₃-C₆-alkyl or C₂-C₆-alkyl which carries one radical selected from the group consisting of C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and the radical NR^(a1)R^(a2), where R^(a1) and R^(a2) are independently of each other selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl.
 14. The compound of claim 1, wherein R^(a) is a radical NR^(a3)R^(a4), where R^(a3) is selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl; R^(a4) is selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 7-membered, saturated heterocyclyl, 3- to 7-membered, saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the heterocycicyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R^(ac), where R^(ac) has one of the meanings given for R^(1c).
 15. The compound of claim 1, wherein R^(b) is hydrogen.
 16. The compound of claim 1 of the formula Ia

wherein Z, Q, R¹, R³, R⁴, R⁵ and R^(a) are as defined above.
 17. A pharmaceutical composition comprising a carrier and a compound of claim
 1. 18. The compound of claim 1 , selected from the group consisting of 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one; 5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)ethyl)isoindolin-1-one; 5-((4-phenoxypyridin-3-yl)methoxy)-2-propylisoindolin-1-one; 2-butyl-5-((2-chloro-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one; 2-butyl-5-((2-chloro-4-iodopyridin-3-yl)methoxy)isoindolin-1-one; 5-(4-Phenyl-pyridin-3-ylmethoxy)-2-propyl-2,3-dihydro-isoindol-1-one; 5-(4-Phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one; [3-(1-oxo-2-propyl-2,3-dihydro-1H-isoindo1-5-yloxymethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester, trifluoroacetate; 2-Butyl-5-(2,6-dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one; 5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxyethyl)-2,3-dihydro-isoindol-1-one, trifluoroacetate; 5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-ethyl-2,3-dihydroisoindol-1-one; 5-[(4-methoxypyridin-3-yl)methoxy]-2-propyl-2,3-dihydro-1H-isoindol-1-one; 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one; 2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one; 2-butyl-5-((4-phenylpyridin-3-yl)methylamino)isoindolin-1-one; 2-butyl-5-((4-phenoxypyridin-3-yl)methylamino)isoindolin-1-one; 2-butyl-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)methylamino)-isoindolin-1-one; 5-((4-aminopyridin-3-yl)methylamino)-2-butylisoindolin-1-one; 2-butyl-5-((4-(phenylamino)pyridin-3-yl)methylamino)isoindolin-1-one; 4-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)benzonitrile; 2-butyl-5-((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methylamino)-isoindolin-1-one; 7-chloro-2-cyclopropyl-5-{[(2,6-dimethyl-4-phenylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one; 7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-cyclopropyl-2,3-dihydro-1H-isoindol-1-one; 2-butyl-5-({[4-(morpholin-4-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one; 2-butyl-5-({[4-(4-methylpiperazin-1-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1 -one; 2-butyl-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2,3-dihydro-1H-isoindol-1-one; 2-butyl-7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one; 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one; 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-propyl-2,3-dihydro-1H-isoindol-1-one; 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-ethyl-7-methyl-2,3-dihydro-1H-isoindol-1-one; 2-butyl-5-{[(2-chloro-4-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one; 2-butyl-5-{[(2,4-dichloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one; 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-7-methyl-2,3-dihydro-1H-isoindol-1-one; 2-butyl-5-{[(2,4-dichloro-6-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one; 5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one; 5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one; N-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)pivalamide; 2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)-methyl)-4-phenylpyridine 1-oxide; 7-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-1-one; 2-Butyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; 7-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-propyl-2,3-dihydro-isoindol-1-one; 2-Ethyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; 2-Butyl-5-[(2-methyl-4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; 2-Butyl-5-[(4-[1,4]oxazepan-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one; 2-Butyl-5-({4-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one; 2-Butyl-5-({4-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one; 2-Butyl-5-({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one; 2-Butyl-5-(4-methoxy-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one; and 2-Butyl-5-(4-morpholin-4-yl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt or N-oxide thereof.
 19. A method for treating a medical disorder, selected from the group consisting of anxiety, depression, schizophrenia, and epilepsy in a mammalian, said method comprising administering an effective amount of at least one compound of claim 1 to a subject in need thereof. 